2-substituted-p-quinone derivatives for treatment of oxidative stress diseases

ABSTRACT

Methods of treating or suppressing oxidative stress diseases including mitochondrial diseases, impaired energy processing disorders, neurodegenerative diseases and diseases of aging are disclosed, as well as compounds useful in the methods of the invention, such as 2-substituted-p-quinone derivatives as disclosed herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Non-Provisional patentapplication Ser. No. 12/919,007, submitted under 35 U.S.C. §371 as aU.S. National Stage Application of International Application No.PCT/US2009/036051 and having an International Filing Date of Mar. 4,2009, and which claims priority benefit of U.S. Provisonal PatentApplication Ser. No. 61/068,333, filed Mar. 5, 2008, of U.S. ProvisionalPatent Application Ser. No. 61/133,216, filed Jun. 25, 2008, and of U.S.Provisional Patent Application Ser. No. 61/194,334, filed Sep. 26, 2008.The entire contents of those applications are hereby incorporated byreference herein.

TECHNICAL FIELD

The application discloses compositions and methods useful for treatment,prevention, or suppression of diseases, developmental delays andsymptoms related to oxidative stress affecting normal electron flow inthe cells. Examples of such diseases are mitochondrial disorders,impaired energy processing disorders, neurodegenerative diseases anddiseases of aging.

BACKGROUND

Oxidative stress is caused by disturbances to the normal redox statewithin cells. An imbalance between routine production and detoxificationof reactive oxygen species such as peroxides and free radicals canresult in oxidative damage to the cellular structure and machinery. Themost important source of reactive oxygen species under normal conditionsin aerobic organisms is probably the leakage of activated oxygen frommitochondria during normal oxidative respiration. Impairments associatedwith this process are suspected to contribute to mitochondrial disease,neurodegenerative disease, and diseases of aging.

Mitochondria are organelles in eukaryotic cells, popularly referred toas the “powerhouse” of the cell. One of their primary functions isoxidative phosphorylation. The molecule adenosine triphosphate (ATP)functions as an energy “currency” or energy carrier in the cell, andeukaryotic cells derive the majority of their ATP from biochemicalprocesses carried out by mitochondria. These biochemical processesinclude the citric acid cycle (the tricarboxylic acid cycle, or Krebscycle), which generates reduced nicotinamide adenine dinucleotide(NADH+H⁺) from oxidized nicotinamide adenine dinucleotide (NAD⁺), andoxidative phosphorylation, during which NADH+H⁺ is oxidized back toNAD⁺. (The citric acid cycle also reduces flavin adenine dinucleotide,or FAD, to FADH₂; FADH₂ also participates in oxidative phosphorylation.)

The electrons released by oxidation of NADH+H⁺ are shuttled down aseries of protein complexes (Complex I, Complex II, Complex III, andComplex IV) known as the mitochondrial respiratory chain. Thesecomplexes are embedded in the inner membrane of the mitochondrion.Complex IV, at the end of the chain, transfers the electrons to oxygen,which is reduced to water. The energy released as these electronstraverse the complexes is used to generate a proton gradient across theinner membrane of the mitochondrion, which creates an electrochemicalpotential across the inner membrane. Another protein complex, Complex V(which is not directly associated with Complexes I, II, III and IV) usesthe energy stored by the electrochemical gradient to convert ADP intoATP.

When cells in an organism are temporarily deprived of oxygen, anaerobicrespiration is utilized until oxygen again becomes available or the celldies. The pyruvate generated during glycolysis is converted to lactateduring anaerobic respiration. The buildup of lactic acid is believed tobe responsible for muscle fatigue during intense periods of activity,when oxygen cannot be supplied to the muscle cells. When oxygen againbecomes available, the lactate is converted back into pyruvate for usein oxidative phosphorylation.

Oxygen poisoning or toxicity is caused by high concentrations of oxygenthat may be damaging to the body and increase the formation offree-radicals and other structures such as nitric oxide, peroxynitrite,and trioxidane. Normally, the body has many defense systems against suchdamage but at higher concentrations of free oxygen, these systems areeventually overwhelmed with time, and the rate of damage to cellmembranes exceeds the capacity of systems which control or repair it.Cell damage and cell death then results.

Qualitative and/or quantitative disruptions in the transport of oxygento tissues result in energy disruption in the function of red cells andcontribute to various diseases such as haemoglobinopathies.Haemoglobinopathy is a kind of genetic defect that results in abnormalstructure of one of the globin chains of the hemoglobin molecule. Commonhaemoglobinopathies include thalassemia and sickle-cell disease.Thalassemia is an inherited autosomal recessive blood disease. Inthalassemia, the genetic defect results in reduced rate of synthesis ofone of the globin chains that makes up hemoglobin. While thalassemia isa quantitative problem of too few globins synthesized, sickle-celldisease is a qualitative problem of synthesis of an incorrectlyfunctioning globin. Sickle-cell disease is a blood disordercharacterized by red blood cells that assume an abnormal, rigid, sickleshape. Sickling decreases the cells' flexibility and results in theirrestricted movement through blood vessels, depriving downstream tissuesof oxygen.

Mitochondrial dysfunction contributes to various disease states. Somemitochondrial diseases are due to mutations or deletions in themitochondrial genome. If a threshold proportion of mitochondria in thecell is defective, and if a threshold proportion of such cells within atissue have defective mitochondria, symptoms of tissue or organdysfunction can result. Practically any tissue can be affected, and alarge variety of symptoms may be present, depending on the extent towhich different tissues are involved. Some examples of mitochondrialdiseases are Friedreich's ataxia (FRDA), Leber's Hereditary OpticNeuropathy (LHON), mitochondrial myopathy, encephalopathy, lactacidosis,and stroke (MELAS), Myoclonus Epilepsy Associated with Ragged-Red Fibers(MERRF) syndrome, Maternally Inherited Diabetes and Deafness (MIDD), andrespiratory chain disorders. Most mitochondrial diseases involvechildren who manifest the signs and symptoms of accelerated aging,including neurodegenerative diseases, stroke, blindness, hearing orbalance impairment, diabetes, and heart failure.

Friedreich's ataxia is an autosomal recessive neurodegenerative andcardiodegenerative disorder caused by decreased levels of the proteinFrataxin. The disease causes the progressive loss of voluntary motorcoordination (ataxia) and cardiac complications. Symptoms typicallybegin in childhood, and the disease progressively worsens as the patientgrows older; patients eventually become wheelchair-bound due to motordisabilities.

Leber's Hereditary Optic Neuropathy (LHON) is a disease characterized byblindness which occurs on average between 27 and 34 years of age. Othersymptoms may also occur, such as cardiac abnormalities and neurologicalcomplications.

Mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS)can manifest itself in infants, children, or young adults. Strokes,accompanied by vomiting and seizures, are one of the most serioussymptoms; it is postulated that the metabolic impairment of mitochondriain certain areas of the brain is responsible for cell death andneurological lesions, rather than the impairment of blood flow as occursin ischemic stroke.

Myoclonus Epilepsy Associated with Ragged-Red Fibers (MERRF) syndrome isone of a group of rare muscular disorders that are called mitochondrialencephalomyopathies. Mitochondrial encephalomyopathies are disorders inwhich a defect in the genetic material arises from a part of the cellstructure that releases energy (mitochondria). This can cause adysfunction of the brain and muscles (encephalomyopathies). Themitochondrial defect as well as “ragged-red fibers” (an abnormality oftissue when viewed under a microscope) are always present. The mostcharacteristic symptom of MERRF syndrome is myoclonic seizures that areusually sudden, brief, jerking, spasms that can affect the limbs or theentire body, difficulty speaking (dysarthria), optic atrophy, shortstature, hearing impairment, dementia, and involuntary jerking of theeyes (nystagmus) may also occur.

Leigh's disease is a rare inherited neurometabolic disordercharacterized by degeneration of the central nervous system where thesymptoms usually begin between the ages of 3 months to 2 years andprogress rapidly. In most children, the first signs may be poor suckingability and loss of head control and motor skills. These symptoms may beaccompanied by loss of appetite, vomiting, irritability, continuouscrying, and seizures. As the disorder progresses, symptoms may alsoinclude generalized weakness, lack of muscle tone, and episodes oflactic acidosis, which can lead to impairment of respiratory and kidneyfunction. Heart problems may also occur.

Maternally Inherited Diabetes and Deafness (MIDD) is caused by amutation in mitochondrial DNA (3243 tRNA). The diabetes is a non insulindependent type that usually presents before the age of 40 years; it isdue to a defect in beta cell function with normal insulin sensitivity.The associated deafness is sensorineural and develops in most of thediabetic subjects. Hearing loss is variable, but can require a hearingaid. In keeping with other mitochondrial disorders, MIDD may have othermulti-organ features: for example, elevated serum lactate, neuromuscularand cardiac problems, pigmented retinopathy, and nephropathy withproteinuria.

Co-Enzyme Q10 Deficiency is a respiratory chain disorder, with syndromessuch as myopathy with exercise intolerance and recurrent myoglobin inthe urine manifested by ataxia, seizures or mental retardation andleading to renal failure (Di Mauro et al., (2005) Neuromusc. Disord.,15:311-315), childhood-onset cerebellar ataxia and cerebellar atrophy(Masumeci et al., (2001) Neurology 56:849-855 and Lamperti et al.,Neurology (2003) 60:1206:1208); and infantile encephalomyopathyassociated with nephrosis. Biochemical measurement of muscle homogenatesof patients with CoQ10 deficiency showed severely decreased activitiesof respiratory chain complexes I and II+III, while complex IV (COX) wasmoderately decreased (Gempel et al., (2007) Brain, 130(8):2037-2044).

Complex I Deficiency or NADH dehydrogenase NADH-CoQ reductase deficiencyis a respiratory chain disorder, with symptoms classified by three majorforms: (1) fatal infantile multisystem disorder, characterized bydevelopmental delay, muscle weakness, heart disease, congenital lacticacidosis, and respiratory failure; (2) myopathy beginning in childhoodor in adult life, manifesting as exercise intolerance or weakness; and(3) mitochondrial encephalomyopathy (including MELAS), which may beginin childhood or adult life and consists of variable combinations ofsymptoms and signs, including ophthalmoplegia, seizures, dementia,ataxia, hearing impairment, pigmentary retinopathy, sensory neuropathy,and uncontrollable movements.

Complex II Deficiency or Succinate dehydrogenase deficiency is arespiratory chain disorder with symptoms including encephalomyopathy andvarious manifestations, including failure to thrive, developmentaldelay, hyoptonia, lethargy, respiratory failure, ataxia, myoclonus andlactic acidosis.

Complex III Deficiency or Ubiquinone-cytochrome C oxidoreductasedeficiency is a respiratory chain disorder with symptoms categorized infour major forms: (1) fatal infantile encephalomyopathy, congenitallactic acidosis, hypotonia, dystrophic posturing, seizures, and coma;(2) encephalomyopathies of later onset (childhood to adult life):various combinations of weakness, short stature, ataxia, dementia,hearing impairment, sensory neuropathy, pigmentary retinopathy, andpyramidal signs; (3) myopathy, with exercise intolerance evolving intofixed weakness; and (4) infantile histiocytoid cardiomyopathy.

Complex IV Deficiency or Cytochrome C oxidase deficiency is arespiratory chain disorder with symptoms categorized in two major forms:(1) encephalomyopathy, which is typically normal for the first 6 to 12months of life and then show developmental regression, ataxia, lacticacidosis, optic atrophy, ophthalmoplegia, nystagmus, dystonia, pyramidalsigns, respiratory problems and frequent seizures; and (2) myopathy withtwo main variants: (a) fatal infantile myopathy—may begin soon afterbirth and accompanied by hypotonia, weakness, lactic acidosis,ragged-red fibers, respiratory failure, and kidney problems: and (b)benign infantile myopathy—may begin soon after birth and accompanied byhypotonia, weakness, lactic acidosis, ragged-red fibers, respiratoryproblems, but (if the child survives) followed by spontaneousimprovement.

Complex V Deficiency or ATP synthase deficiency is a respiratory chaindisorder including symptoms such as slow, progressive myopathy.

CPEO or Chronic Progressive External Ophthalmoplegia Syndrome is arespiratory chain disorder including symptoms such as visual myopathy,retinitis pigmentosa, or dysfunction of the central nervous system.

Kearns-Sayre Syndrome (KSS) is a mitochondrial disease characterized bya triad of features including: (1) typical onset in persons younger thanage 20 years; (2) chronic, progressive, external ophthalmoplegia; and(3) pigmentary degeneration of the retina. In addition, KSS may includecardiac conduction defects, cerebellar ataxia, and raised cerebrospinalfluid (CSF) protein levels (e.g., >100 mg/dL). Additional featuresassociated with KSS may include myopathy, dystonia, endocrineabnormalities (e.g., diabetes, growth retardation or short stature, andhypoparathyroidism), bilateral sensorineural deafness, dementia,cataracts, and proximal renal tubular acidosis.

In addition to congenital disorders involving inherited defectivemitochondria, acquired mitochondrial dysfunction contributes todiseases, particularly neurodegenerative disorders associated with aginglike Parkinson's, Alzheimer's, and Huntington's Diseases. The incidenceof somatic mutations in mitochondrial DNA rises exponentially with age;diminished respiratory chain activity is found universally in agingpeople. Mitochondrial dysfunction is also implicated in excitoxic,neuronal injury, such as that associated with cerebral vascularaccidents, seizures and ischemia.

Other recent studies have suggested that as many 20 percent of patientswith pervasive development disorders such as autism have markers formitochondrial disease, (Shoffner, J. the 60^(th) Annual American Academyof Neurology meeting in Chicago, Apr. 12-19, 2008; Poling, J S et al J.child Neurol. 2008, 21(2) 170-2; and Rossignol et al., Am. J. Biochem. &Biotech. (2008)4, 208-217.) Some cases of autism have been associatedwith bioenergetic metabolism deficiency suggested by the detection ofhigh lactate levels in some patients (Coleman M. et al, Autism andLactic Acidosis, J. Autism Dev Disord., (1985) 15: 1-8; Laszlo et alSerum serotonin, lactate and pyruvate levels in infantile autisticchildren, Clin. Chim. Acta (1994) 229:205-207; and Chugani et al.,Evidence of altered energy metabolism in autistic children, Progr.Neuropsychopharmacol Biol Psychiat., (1999) 23:635-641) and by nuclearmagnetic resonance imagining as well as positron emission tomographyscanning which documented abnormalities in brain metabolism.

Genetic mitochondrial mutations have also been correlated to hearingimpairment. This has been demonstrated by the presence of mitochondrialDNA mutations in families with non-syndromic progressive sensorineuralhearing loss (SNHL) (Berretinin, S. et al., Biosci. Rep. (2008) 28.45-59 and Guan M, et al, Human Mol Gen 2000, 9, 12, 1787-93).Involvement of mitochondrial pathways in cisplatin-induced apoptosis ina model in vitro system of cultured auditory cells is suggested byDevarjan et al. (Hearing Research, (2002) 174, 45-54). Involvement ofthe mitochondrial permeability transition in gentamicin-inducedapoptosis is suggested by Dehne et al., (Hearing Research (2002) 169.47-55).

The diseases above appear to be caused by defects in Complex I of therespiratory chain. Electron transfer from Complex I to the remainder ofthe respiratory chain is mediated by the compound coenzyme Q (also knownas Ubiquinone). Oxidized coenzyme Q (CoQ^(ox) or Ubiquinone) is reducedby Complex I to reduced coenzyme Q (CoQ^(red) or Ubiquinol). The reducedcoenzyme Q then transfers its electrons to Complex III of therespiratory chain (skipping over complex II), where it is re-oxidized toCoQ^(ox) (Ubiquinone). CoQ^(ox) can then participate in furtheriterations of electron transfer.

Very few treatments are available for patients suffering from thesemitochondrial diseases. Recently, the compound Idebenone has beenproposed for treatment of Friedreich's ataxia. While the clinicaleffects of Idebenone have been relatively modest, the complications ofmitochondrial diseases can be so severe that even marginally usefultherapies are preferable to the untreated course of the disease. Anothercompound, MitoQ, has been proposed for treating mitochondrial disorders(see U.S. Pat. No. 7,179,928); clinical results for MitoQ have not yetbeen reported. Administration of coenzyme Q10 (CoQ10) and vitaminsupplements has shown only transient beneficial effects in individualcases of KSS. CoQ10 supplementation has also been used for the treatmentof CoQ10 deficiency with mixed results.

Oxidative stress is suspected to be important in neurodegenerativediseases such as Motor Neuron Disease, Amyotrophic Lateral Sclerosis(ALS)), Creutzfeldt-Jakob disease, Machado-Joseph disease,Spino-cerebellar ataxia, Multiple sclerosis (MS), Parkinson's disease,Alzheimer's disease, and Huntington's disease. Oxidative stress isthought to be linked to certain cardiovascular disease and also plays arole in the ischemic cascade due to oxygen reperfusion injury followinghypoxia. This cascade includes both strokes and heart attacks.

Damage accumulation theory, also known as the free radical theory ofaging, invokes random effects of free radicals produced during aerobicmetabolism that cause damage to DNA, lipids and proteins and accumulateover time. The concept of free radicals playing a role in the agingprocess was first introduced by Himan D., (1956), Aging—A theory basedon free-radical and radiation chemistry J. Gerontol., 11, 298-300.

According to the free radical theory of aging, the process of agingbegins with oxygen metabolism (Valko et al, (2004) Role of oxygenradicals in DNA damage and cancer incidence, Mol. Cell. Biochem., 266,37-56). Even under ideal conditions some electrons “leak” from theelectron transport chain. These leaking electrons interact with oxygento produce superoxide radicals, so that under physiological conditions,about 1-3% of the oxygen molecules in the mitochondria are convertedinto superoxide. The primary site of radical oxygen damage fromsuperoxide radical is mitochondrial DNA (mtDNA) (Cadenas et al., (2000)Mitochondrial free radical generation, oxidative stress and aging, FreeRadic. Res, 28, 601-609). The cell repairs much of the damage done tonuclear DNA (nDNA) but mtDNA cannot be fixed. Therefore, extensive mtDNAdamage accumulates over time and shuts down mitochondria causing cellsto die and organism to age.

Some of the diseases associated with increasing age are cancer, diabetesmellitus, hypertension, atherosclerosis, ischemia/reperfusion injury,rheumatoid arthritis, neurodegenerative disorders such as dementia,Alzheimer's and Parkinson's. Diseases resulting from the process ofaging as a physiological decline include decreases in muscle strength,cardiopulmonary function, vision and hearing as well as wrinkled skinand graying hair.

The ability to adjust biological production of energy has applicationsbeyond the diseases described above. Various other disorders can resultin suboptimal levels of energy biomarkers (sometimes also referred to asindicators of energetic function), such as ATP levels. Treatments forthese disorders are also needed, in order to modulate one or more energybiomarkers to improve the health of the patient. In other applications,it can be desirable to modulate certain energy biomarkers away fromtheir normal values in an individual that is not suffering from disease.For example, if an individual is undergoing an extremely strenuousundertaking, it can be desirable to raise the level of ATP in thatindividual.

DISCLOSURE OF THE INVENTION

The present invention embraces compounds of Formula Q and Formula HQ,

where,

-   A is (C₁-C₄)-alkylene, (C₂-C₄)-alkenylene, or (C₂-C₄)-alkynylene;-   Z is —BR³⁰, —BR³⁶, or —NR⁴R⁵;-   B is selected from —C(O)NR⁴—, C(O)NR³⁵—, —NR⁴C(O)—, —NR⁴C(O)NR⁴—,    —NR⁴SO₂—, —SO₂NR⁴—, and —SO₂NR³⁵—;-   R³⁰ is hydrogen, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,    aryl, or heterocyclyl,    -   where the alkyl, alkenyl or alkynyl groups may optionally be        substituted with —OR¹⁰, —SR¹⁰, —CN, —F, —Cl, —Br, —I,        —NR¹⁰R^(10′), oxo, (C₃-C₆)-cycloalkyl, aryl, aryl-(C₁-C₆)-alkyl,        heteroaryl, heterocyclyl, —C(O)—R¹¹, —C(O)—C₀-C₆-alkyl-aryl,        —C(O)—O—R¹¹, —C(O)—O—(C₀-C₆)-alkyl-aryl, —C(O)—N—R¹¹R^(11′),        —C(O)—N—(C₀-C₆)-alkyl-aryl, —N—C(O)—R¹¹,        —N—C(O)—(C₀-C₆)-alkyl-aryl; or where one of the carbons of the        alkyl, alkenyl, or alkynyl groups may be replaced by a        heteroatom selected from O, N or S; and        -   where the aryl, heteroaryl and heterocyclyl rings may be            further substituted with (C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl,            —CN, —F, —Cl, —Br, —I, —NR¹⁰R^(10′), oxo, hydroxy,            (C₁-C₆)-alkoxy, —C(O)—(C₁-C₆)-alkyl, —C(O)—O—H, and            —C(O)—O—(C₁-C₆)-alkyl; or-   R³⁰ and R⁴ together with the atom to which they are attached form a    saturated or unsaturated 3-8 membered ring, optionally incorporating    one or more additional heteroatoms independently selected from one,    two, or three, N, O, or S atoms, and optionally substituted with    oxo, —OR¹⁰, —SR¹⁰, —CN, —F, —Cl, —Br, —I, —NR¹⁰R^(10′),    (C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl; hydroxy-(C₁-C₆)-alkyl, —C(O)—H,    —C(O)—(C₁-C₆)-alkyl, —C(O)—OH, or —C(O)—O—(C₁-C₆)-alkyl;-   R¹ is (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, heterocyclyl or aryl, where the    heterocyclyl and the aryl are optionally substituted with one or    more substituents independently selected from —OH, (C₁-C₆)-alkyl,    (C₁-C₆)-alkoxy, hydroxy-(C₁-C₆)alkyl-, alkoxy-(C₁-C₆)-alkyl-,    —NR¹⁰R^(10′), —(C₁-C₆)-alkyl —NR¹⁰R^(10′), —C(O)—(C₁-C₆)-alkyl,    —C(O)—OH, —C(O)O—(C₁-C₆)-alkyl, —C(O)NR¹⁰R^(10′), —NR¹¹C(O)R¹⁰,    —NR¹¹C(O)NR¹⁰R^(10′), —NR¹¹C(O)OR¹⁰, —SO₂(C₁-C₆)-alkyl,    —SO₂(C₁-C₆)-haloalkyl, —SO₂-aryl, —SO₂NR¹⁰R^(10′), CN, haloalkyl,    and halogen;-   R² is hydrogen, (C₁-C₆)-alkyl, or (C₁-C₆)-alkoxy;-   R³ is unsubstituted (C₁-C₆)-alkyl or (C₁-C₆)-alkyl substituted with    hydroxy;-   R⁴ is hydrogen or (C₁-C₆)-alkyl;-   R⁵ is —C(O)—R⁶, —SO₂—R⁶, —C(O)OR⁶, or —C(O)NR⁶R⁷;-   R⁶ is hydrogen, (C₁-C₆)-alkyl, aryl, or heterocyclyl, where    -   (C₁-C₆)-alkyl is optionally substituted with one or more        substituents independently selected from        -   —OR¹¹, —SR¹¹, —CN, —F, —Cl, —Br, —I, —NR¹⁰R^(10′),            (C₃-C₆)-cycloalkyl, aryl, heterocyclyl, —C(O)—R¹¹,            —C(O)—(C₀-C₆)-alkyl-aryl, —C(O)O—R¹¹,            —C(O)—O—(C₀-C₆)-alkyl-aryl, —C(O)N—R¹⁰R^(10′),            —C(O)NR¹¹—(C₀-C₆)-alkyl-aryl, —NR¹¹C(O)—R¹⁰, and            —NR¹¹C(O)—(C₀-C₆)-alkyl-aryl; wherein the aryl and            heterocyclyl ring substituents may be further substituted            with one or more groups independently selected from            (C₁-C₆)-alkyl, halogen, (C₁-C₆)-haloalkyl, oxo, CN, hydroxy,            (C₁-C₆)-alkoxy, —C(O)—(C₁-C₆)-alkyl, and            —C(O)—O—(C₁-C₆)-alkyl; and where    -   aryl and heterocyclyl are optionally substituted with        (C₁-C₆)-alkyl, halogen, (C₁-C₆)-haloalkyl, CN, oxo, hydroxy,        (C₁-C₆)-alkoxy, —C(O)—(C₁-C₆)-alkyl and —C(O)—O—(C₁-C₆)-alkyl;-   R⁷ is hydrogen or (C₁-C₆)-alkyl; or-   R⁶ and R⁷ together with the atom to which they are attached form a    saturated or unsaturated 3-8 membered ring, optionally incorporating    one or more additional heteroatoms independently selected from one,    two, or three, N, O, or S atoms, and optionally substituted with    oxo, —OH, —SH, —F, —Cl, —Br, —I, —NR¹¹R^(11′), (C₁-C₆)-alkyl,    (C₁-C₆)-alkoxy; (C₁-C₆)-thioalkyl, (C₁-C₆)-haloalkyl;    hydroxy-(C₁-C₆)-alkyl, —C(O)—H, —C(O)—(C₁-C₆)-alkyl, —C(O)OH, or    —C(O)O—(C₁-C₆)-alkyl;-   R¹⁰ and R^(10′) are independently selected from the group consisting    of H, (C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl, aryl, aryl-(C₁-C₆)-alkyl,    heteroaryl, heterocyclyl, —C(O)—H, —C(O)—(C₁-C₆)-alkyl, —C(O)-aryl,    and —C(O)—(C₁-C₆)-alkyl-aryl; or-   R¹⁰ and R^(10′) together with the atom to which they are attached    form a saturated or unsaturated 3-8 membered ring, optionally    incorporating one or more additional heteroatoms independently    selected from one, two, or three, N, O, or S atoms, and optionally    substituted with one or more substituents independently selected    from oxo, —OH, —F, —Cl, —Br, —I, —NR¹¹R^(11′), (C₁-C₆)-alkyl,    (C₁-C₆)-alkoxy; (C₁-C₆)-haloalkyl; hydroxy-(C₁-C₆)-alkyl, —C(O)—H,    —C(O)—(C₁-C₆)-alkyl, —C(O)OH, and —C(O)O—(C₁-C₆)-alkyl;-   R¹¹ and R^(11′) are independently selected from hydrogen and    (C₁-C₆)-alkyl; or-   R¹¹ and R^(11′) together with the atom to which they are attached    form a saturated or unsaturated 3-8 membered ring, optionally    incorporating one or more additional, such as one, two, or three, N,    O, or S atoms and optionally substituted with oxo, —OR¹⁰, —SR¹⁰,    —CN, —F, —Cl, —Br, —I, —NH₂, —NH(C₁-C₄)-alkyl, —N((C₁-C₄)-alkyl)₂,    (C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl; hydroxy-(C₁-C₆)-alkyl, —C(O)—H,    —C(O)—(C₁-C₆)-alkyl, —C(O)—OH, or —C(O)—O—(C₁-C₆)-alkyl;-   R³⁵ and R³⁶ are independently selected from hydrogen, hydroxy,    alkoxy, (C₁-C₄₀)-alkyl, (C₂-C₄₀)-alkenyl, (C₂-C₄₀)-alkynyl, aryl or    heterocyclyl;    -   where the alkyl, alkenyl or alkynyl groups may optionally be        substituted with:        -   —OR¹⁰, —SR¹⁰, —CN, —F, —Cl, —Br, —I, —NR^(10a)R^(10b), oxo,            C₃-C₆-cycloalkyl, aryl, aryl-(C₁-C₆)-alkyl, heteroaryl,            heterocyclyl, —C(O)—R¹¹, —C(O)—C₀-C₆-alkyl-aryl,            —C(O)—O—R¹¹, —C(O)—O—C₀-C₆-alkyl-aryl,            —C(O)—N—R^(11a)R^(11b), —C(O)—N—C₀-C₆-alkyl-aryl,            —N—C(O)—R¹¹, —N—C(O)—C₀-C₆-alkyl-aryl; and    -   where the aryl, heteroaryl and heterocyclyl rings may be further        substituted with (C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl, —CN, —F, —Cl,        —Br, —I, —NR^(10a)R^(10b), oxo, hydroxy, (C₁-C₆)-alkoxy,        —C(O)—(C₁-C₆)-alkyl and —C(O)—O—(C₁-C₆)-alkyl; and    -   where one of the carbons of the alkyl, alkenyl, or alkynyl        groups may be replaced by a heteroatom selected from O, N or S;        or-   R³⁵ and R³⁶ together with the atom to which they are attached form a    saturated or unsaturated 3-8 membered ring, optionally incorporating    one or more additional heteroatoms independently selected from one,    two, or three, N, O, or S atoms, and optionally substituted with    oxo, —OR¹⁰, —SR¹⁰, —CN, —F, —Cl, —Br, —I, —NR^(10a)R^(10b),    (C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl; hydroxy-(C₁-C₆)-alkyl, —C(O)—H,    —C(O)—(C₁-C₆)-alkyl, —C(O)—OH, or —C(O)—O—(C₁-C₆)-alkyl;    and-   M and M′ are independently selected from hydrogen, —C(O)—R′,    —C(O)—(C₂-C₆)-alkenyl, —C(O)—(C₂-C₆)-alkynyl, —C(O)-aryl,    —C(O)-heterocyclyl, —C(O)O—R′, —C(O)NR′R″, —SO₂OR′,    —SO₂(C₁-C₆)-alkyl, —SO₂(C₁-C₆)-haloalkyl, —SO₂-aryl, —SO₂NR′R″,    —P(O)(OR′)(OR″), and C-linked mono- or di-peptide, where R′ and R″    are independently of each other hydrogen or (C₁-C₆)-alkyl optionally    substituted with one or more substituents independently selected    from —OH, —NH₂, —NH(C₁-C₄)-alkyl, —N((C₁-C₄)-alkyl)₂, —C(O)OH,    —C(O)O—(C₁-C₄)-alkyl, and halogen;    and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates, and hydrates thereof.

In some embodiments, the invention embraces compounds of Formula Q andQH, wherein the following compounds are excluded:

-   N-(4-(1H-imidazol-1-yl)phenyl)-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)propanamide;    N-(2-(4-decylpiperazin-1-yl)-1-phenylethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    N-(2-(4-(10-hydroxydecyl)piperazin-1-yl)-1-phenylethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    N-(2-(4-(10-hydroxydecyl)piperazin-1-yl)-2-oxo-1-phenylethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    N-(4-hydroxy-3,5-dimethylphenyl)-5-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)pentanamide;    and    5-(2,5-dihydroxy-3,4,6-trimethylphenyl)-N-(4-hydroxy-3,5-dimethylphenyl)pentanamide.

In one embodiment, the invention embraces compounds of Formula I:

where,

-   R is selected from the group consisting of:

where the * indicates the point of attachment of R to the remainder ofthe molecule;

-   M and M′ are independently selected from hydrogen, —C(O)—R′,    —C(O)—(C₂-C₆)-alkenyl, —C(O)—(C₂-C₆)-alkynyl, —C(O)-aryl,    —C(O)-heterocyclyl, —C(O)O—R′, —C(O)NR′R″, —SO₂OR′,    —SO₂(C₁-C₆)-alkyl, —SO₂(C₁-C₆)-haloalkyl, —SO₂-aryl, —SO₂NR′R″,    —P(O)(OR′)(OR″), and C-linked mono- or di-peptide, where R′ and R″    are independently of each other hydrogen or (C₁-C₆)-alkyl optionally    substituted with one or more substituents independently selected    from —OH, —NH₂, —NH(C₁-C₄)-alkyl, —N((C₁-C₄)-alkyl)₂, —C(O)OH,    —C(O)O—(C₁-C₄)-alkyl, and halogen;-   R¹ is (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, heterocyclyl or aryl, where the    heterocyclyl and the aryl are optionally substituted with one or    more substituents independently selected from —OH, (C₁-C₆)-alkyl,    (C₁-C₆)-alkoxy, hydroxy-(C₁-C₆)alkyl-, alkoxy(C₁-C₆)alkyl-,    —NR¹⁰R^(10′), —(C₁-C₆)-alkyl —NR¹⁰R^(10′), —C(O)—(C₁-C₆)-alkyl,    —C(O)—OH, —C(O)O—(C₁-C₆)-alkyl, —C(O)NR¹⁰R^(10′), —NR¹¹C(O)R¹⁰,    —NR¹¹C(O)NR¹⁰R^(10′), —NR¹¹C(O)OR¹⁰, —SO₂(C₁-C₆)-alkyl,    —SO₂(C₁-C₆)-haloalkyl, —SO₂-aryl, —SO₂NR¹⁰R^(10′), CN, haloalkyl,    and halogen;-   R² is hydrogen, (C₁-C₆)-alkyl, or (C₁-C₆)-alkoxy;-   R³ is unsubstituted (C₁-C₆)-alkyl;-   R⁴ is hydrogen or (C₁-C₆)-alkyl;-   R⁵ is —C(O)—R⁶, —SO₂—R⁶, —C(O)OR⁶, or —C(O)NR⁶R⁷;-   R⁶ is hydrogen, (C₁-C₆)-alkyl, aryl, or heterocyclyl, where    -   (C₁-C₆)-alkyl is optionally substituted with one or more        substituents independently selected from        -   —OR¹¹, —SR¹¹, —CN, —F, —Cl, —Br, —I, —NR¹⁰R^(10′),            (C₃-C₆)-cycloalkyl, aryl, heterocyclyl, —C(O)—R¹¹,            —C(O)—(C₀-C₆)-alkyl-aryl, —C(O)O—R¹¹,            —C(O)—O—(C₀-C₆)-alkyl-aryl, —C(O)N—R¹⁰R^(10′),            —C(O)NR¹¹—(C₀-C₆)-alkyl-aryl, —NR¹¹C(O)—R¹⁰, and            —NR¹¹C(O)—(C₀-C₆)-alkyl-aryl; wherein the aryl and            heterocyclyl ring substituents may be further substituted            with one or more groups independently selected from            (C₁-C₆)-alkyl, halogen, (C₁-C₆)-haloalkyl, CN, oxo, hydroxy,            (C₁-C₆)-alkoxy, —C(O)—(C₁-C₆)-alkyl, and            —C(O)—O—(C₁-C₆)-alkyl; and where    -   aryl and heterocyclyl are optionally substituted with        (C₁-C₆)-alkyl, halogen, (C₁-C₆)-haloalkyl, CN, oxo, hydroxy,        (C₁-C₆)-alkoxy, —C(O)—(C₁-C₆)-alkyl and —C(O)—O—(C₁-C₆)-alkyl;-   R⁷ is hydrogen or (C₁-C₆)-alkyl; or-   R⁶ and R⁷ together with the atom to which they are attached form a    saturated or unsaturated 3-8 membered ring, optionally incorporating    one or more additional heteroatoms independently selected from one,    two, or three, N, O, or S atoms, and optionally substituted with    oxo, —OH, —SH, —F, —Cl, —Br, —I, —NR¹⁰R^(10′), (C₁-C₆)-alkyl,    (C₁-C₆)-alkoxy; (C₁-C₆)-thioalkyl, (C₁-C₆)-haloalkyl;    hydroxy-(C₁-C₆)-alkyl, —C(O)—H, —C(O)—(C₁-C₆)-alkyl, —C(O)OH, or    —C(O)O—(C₁-C₆)-alkyl;-   R¹⁰ and R^(10′) are independently selected from the group consisting    of H, (C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl, aryl, aryl-(C₁-C₆)-alkyl,    heteroaryl, heterocyclyl, —C(O)—H, —C(O)—(C₁-C₆)-alkyl, —C(O)-aryl,    and —C(O)—(C₁-C₆)-alkyl-aryl; or-   R¹⁰ and R^(10′) together with the atom to which they are attached    form a saturated or unsaturated 3-8 membered ring, optionally    incorporating one or more additional heteroatoms independently    selected from one, two, or three, N, O, or S atoms, and optionally    substituted with one or more substituents independently selected    from oxo, —OH, —F, —Cl, —Br, —I, —NR¹¹R^(11′), (C₁-C₆)-alkyl,    (C₁-C₆)-alkoxy; (C₁-C₆)-haloalkyl; hydroxy-(C₁-C₆)-alkyl, —C(O)—H,    —C(O)—(C₁-C₆)-alkyl, —C(O)OH, and —C(O)O—(C₁-C₆)-alkyl;-   R¹¹ and R^(11′) are independently selected from hydrogen and    (C₁-C₆)-alkyl; and-   A is (C₁-C₄)-alkylene, (C₂-C₄)-alkenylene, or (C₂-C₄)-alkynylene;    and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces a method of treating orsuppressing an oxidative stress disorder such as a mitochondrialdisorder, an impaired energy processing disorder, a neurodegenerativedisorder, or a disease of aging, modulating one or more energybiomarkers, normalizing one or more energy biomarkers, or enhancing oneor more energy biomarkers, by administering a therapeutically effectiveamount or effective amount of one or more compounds of Formula I asdescribed above. In some embodiments, the disorder is Friedreich'sataxia. In other embodiments, the disorder is MELAS. In otherembodiments, the disorder is LHON. In other embodiments, the disorder isMERFF. In other embodiments the disorder is MIDD.

In another embodiment, the invention embraces a method of treating orsuppressing a disorder of the respiratory chain. In particularembodiments, the disorder is Coenzyme Q10 deficiency. In otherparticular embodiments, the disorder is a defect of Complex I, orComplex II, or Complex III, or Complex IV, or Complex V, or acombination thereof.

In another embodiment, the invention embraces a method of treatingdiseases caused by energy impairment due to deprivation, poisoning, ortoxicity of oxygen.

In another embodiment, the invention embraces a method of treatingdisorders caused by energy impairment where qualitative and/orquantitative disruptions in the transport of oxygen to tissues result inenergy disruption in the function of red cells. Some of these diseasesinclude haemoglobinopathies, such as sickle-cell disease andthalassemia.

In another embodiment, the invention embraces a method of treating orsuppressing a neurodegenerative disorder. In particular embodiments, theneurodegenerative disorder is a disorder associated with aging. In otherparticular embodiments, the disorder is Huntington's, Parkinson's, orAlzheimer's disease. In other particular embodiments, the disorder isrelated to a neurodegenerative disorder resulting in hearing or balanceimpairment.

In another embodiment, the invention embraces compounds of Formula Ia:

where,

-   R¹ is (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, heterocyclyl, or aryl; where    the heterocyclyl and the aryl are optionally substituted with one or    more substituents independently selected from —OH, (C₁-C₆)-alkyl,    (C₁-C₆)-alkoxy, hydroxy-(C₁-C₆)alkyl-, alkoxy(C₁-C₆)alkyl-,    —NR¹⁰R^(10′), —(C₁-C₆)-alkyl —NR¹⁰R^(10′), —C(O)—(C₁-C₆)-alkyl,    —C(O)—OH, —C(O)O—(C₁-C₆)-alkyl, —C(O)NR¹⁰R^(10′), —NR¹¹C(O)R¹⁰,    —NR¹¹C(O)NR¹⁰R^(10′), —NR¹¹C(O)OR¹⁰, —SO₂(C₁-C₆)-alkyl,    —SO₂(C₁-C₆)-haloalkyl, —SO₂-aryl, —SO₂NR¹⁰R^(10′), CN, haloalkyl,    and halogen;-   R² is hydrogen, (C₁-C₆)-alkyl, or (C₁-C₆)-alkoxy;-   R³ is unsubstituted (C₁-C₆)-alkyl;-   R⁴ is hydrogen or (C₁-C₆)-alkyl;-   R⁵ is —C(O)—R⁶, —SO₂—R⁶, —C(O)O—R⁶, or —C(O)NR⁶R⁷;-   R⁶ is hydrogen, (C₁-C₆)-alkyl, aryl, or heterocyclyl, where    -   (C₁-C₆)-alkyl is optionally substituted with one or more        substituents independently selected from        -   —OR¹¹, —SR¹¹, —CN, —F, —Cl, —Br, —I, —NR¹⁰R^(10′),            (C₃-C₆)-cycloalkyl, aryl, heterocyclyl, —C(O)—R¹¹,            —C(O)—(C₀-C₆)-alkyl-aryl, —C(O)O—R¹¹,            —C(O)—O—(C₀-C₆)-alkyl-aryl, —C(O)N—R¹⁰R^(10′),            —C(O)NR¹¹—(C₀-C₆)-alkyl-aryl, —NR¹¹C(O)—R¹⁰, and            —NR¹¹C(O)—(C₀-C₆)-alkyl-aryl; wherein the aryl and            heterocyclyl ring substituents may be further substituted            with one or more groups independently selected from            (C₁-C₆)-alkyl, halogen, (C₁-C₆)-haloalkyl, CN, oxo, hydroxy,            (C₁-C₆)-alkoxy, —C(O)—(C₁-C₆)-alkyl, and            —C(O)—O—(C₁-C₆)-alkyl; and where    -   aryl and heterocyclyl are optionally substituted with        (C₁-C₆)-alkyl, halogen, (C₁-C₆)-haloalkyl, CN, oxo, hydroxy,        (C₁-C₆)-alkoxy, —C(O)—(C₁-C₆)-alkyl and —C(O)—O—(C₁-C₆)-alkyl;-   R⁷ is hydrogen or (C₁-C₆)-alkyl; or-   R⁶ and R⁷ together with the atom to which they are attached form a    saturated or unsaturated 3-8 membered ring, optionally incorporating    one or more additional heteroatoms independently selected from one,    two, or three, N, O, or S atoms, and optionally substituted with    oxo, —OH, —SH, —F, —Cl, —Br, —I, —NR¹¹R^(11′), (C₁-C₆)-alkyl,    (C₁-C₆)-alkoxy; (C₁-C₆)-thioalkyl, (C₁-C₆)-haloalkyl;    hydroxy-(C₁-C₆)-alkyl, —C(O)—H, —C(O)—(C₁-C₆)-alkyl, —C(O)OH, or    —C(O)O—(C₁-C₆)-alkyl;-   R¹⁰ and R^(10′) are independently selected from H, (C₁-C₆)-alkyl,    (C₁-C₆)-haloalkyl, aryl, aryl-(C₁-C₆)-alkyl, heteroaryl,    heterocyclyl, —C(O)—H, —C(O)—(C₁-C₆)-alkyl, —C(O)-aryl, and    —C(O)—(C₁-C₆)-alkyl-aryl; or-   R¹⁰ and R^(10′) together with the atom to which they are attached    form a saturated or unsaturated 3-8 membered ring, optionally    incorporating one or more additional heteroatoms independently    selected from one, two, or three, N, O, or S atoms, and optionally    substituted with one or more substituents independently selected    from oxo, —OH, —F, —Cl, —Br, —I, —NR¹¹R^(11′), (C₁-C₆)-alkyl,    (C₁-C₆)-alkoxy; (C₁-C₆)-haloalkyl; hydroxy-(C₁-C₆)-alkyl, —C(O)—H,    —C(O)—(C₁-C₆)-alkyl, —C(O)OH, and —C(O)—O—(C₁-C₆)-alkyl;-   R¹¹ and R^(11′) are independently selected from hydrogen and    (C₁-C₆)-alkyl; and-   A is (C₁-C₄)-alkylene, (C₂-C₄)-alkenylene, or (C₂-C₄)-alkynylene;    with the proviso that the compound is not:-   2,2,2-trifluoro-N-((2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)methyl)acetamide;    and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Ia,where A is (C₁-C₄)-alkylene; for example —CH₂—CH₂— or —CH₂—CH₂—CH₂—.

In another embodiment, the invention embraces compounds of Formula Ia,where R¹, R² and R³ are independently selected from methyl, ethyl,n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl,cyclobutyl, cyclopropyl-methyl, methyl-cyclopropyl, pentyl where thepoint of attachment of the pentyl group to the remainder of the moleculecan be at any location on the pentyl fragment, cyclopentyl, hexyl wherethe point of attachment of the hexyl group to the remainder of themolecule can be at any location on the hexyl fragment, and cyclohexyl;and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Ia,where R¹ is optionally substituted aryl, and R² and R³ are independently(C₁-C₆)-alkyl. In some embodiments, R¹ is unsubstituted phenyl. Inanother embodiment, the invention embraces compounds of Formula Ia,where R¹ is phenyl substituted with one or more substituentsindependently selected from (C₁-C₄)-alkyl, halogen, (C₁-C₄)-haloalkyl-,hydroxy, (C₁-C₄)-alkoxy, and —CO(C₁-C₄)-alkyl; and all saltsstereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof. In another embodiment, the inventionembraces compounds of Formula Ia, where R¹ is phenyl substituted withone or more substituents independently selected from (C₁-C₆)-alkyl, suchas methyl; halogen, such as fluoro or chloro; and (C₁-C₆)-haloalkyl,such as CF₃ or CHF₂; and all salts stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof. Insome of the prior embodiments, the phenyl substitution is at the paraposition. In some embodiments, the invention embraces compounds ofFormula Ia, where R² and R³ are methyl; and all salts, stereoisomers,mixtures of stereoisomers, prodrugs, metabolites, solvates, and hydratesthereof.

In another embodiment, the invention embraces compounds of Formula Ia,where R¹ and R² are independently (C₁-C₆)-alkoxy, and R³ isunsubstituted (C₁-C₆)-alkyl; in some embodiments, R¹ is (C₁-C₆)-alkoxyand R² and R³ are independently unsubstituted (C₁-C₄)-alkyl, and in yetanother embodiment, R² is (C₁-C₆)-alkoxy and R¹ and R³ are independentlyunsubstituted (C₁-C₆)-alkyl; and all salts, stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Ia,where R⁵ is selected from —C(O)—(C₁-C₆)-alkyl and —S(O)₂—(C₁-C₆)-alkylwhere the alkyl is optionally substituted with one or more, for example,one, two or three, substituents independently selected from OH, —SH,(C₁-C₄)-alkoxy, (C₁-C₄)-thioalkyl, —CN, —F, —Cl, —Br, —I, —NH₂,—NH(C₁-C₄)-alkyl, and —N((C₁-C₄)-alkyl)₂ and in some embodiments, R⁵ isselected from —C(O)—CH₂—CH₃, —C(O)—CH₂—CH₂—CH₃, —C(O)—CH₂—CH₂—OH,—C(O)—CH₂—CH₂—NH₂, —C(O)—CH₂—CH₂—NH(CH₃), —C(O)—CH₂—CH₂—N(CH₃)₂ and—C(O)—CH₂—CH₂—N(CH₂CH₃)₂; and all salts stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Iawhere R⁵ is selected from —C(O)—(C₁-C₆)-alkyl-aryl and—S(O)₂—(C₁-C₆)-alkyl-aryl, where the aryl group is optionallysubstituted with one or more groups independently selected from(C₁-C₄)-alkyl, OH, —SH, (C₁-C₄)-alkoxy, (C₁-C₄)-thioalkyl, —F, —Cl, —Br,—I, haloalkyl, —NH₂, —NH(C₁-C₄)-alkyl, and —N((C₁-C₄)-alkyl)₂, forexample compounds where R⁵ is benzyl optionally substituted with one ormore groups independently selected from methyl, chloro, fluoro, andtrifluoromethyl.

In another embodiment, the invention embraces compounds of Formula Ia,where R⁵ is —C(O)-aryl or —S(O)₂-aryl where the aryl is optionallysubstituted with one or more groups independently selected from(C₁-C₄)-alkyl, OH, —SH, (C₁-C₄)-alkoxy, (C₁-C₄)-thioalkyl, —F, —Cl, —Br,—I, CN, haloalkyl, —NH₂, —NH(C₁-C₄)-alkyl, and —N((C₁-C₄)-alkyl)₂, forexample where R⁵ is —C(O)phenyl optionally substituted with one or moresubstituents independently selected from fluoro, chloro andtrifluoromethyl, and all salts stereoisomers, mixtures of stereoisomers,prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Ia,where R⁵ is —C(O)OR⁶; and in some embodiments, R⁵ is—C(O)O—(C₁-C₆)-alkyl, —C(O)O—(C₁-C₆)-phenyl, or —C(O)O-phenyl optionallysubstituted with one or more groups independently selected from(C₁-C₆)-alkyl, OR¹⁰, —SR¹⁰, —CN, —F, —Cl, —Br, —I, haloalkyl, and—NR¹⁰R^(10′), and all salts stereoisomers, mixtures of stereoisomers,prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Ia,where R⁵ is —C(O)NR⁶R⁷ where R⁶ and R⁷ are hydrogen and all saltsstereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Ia,where R⁵ is —C(O)NR⁶R⁷ where R⁶ is (C₁-C₆)-alkyl optionally substitutedwith —OR¹⁰, —SR¹⁰, —CN, —F, —Cl, —Br, —I, or —NR¹⁰R^(10′) and R⁷ isindependently (C₁-C₆)-alkyl. In some embodiments, R⁶ and R⁷ areindependently selected from methyl, ethyl, propyl, and butyl, and allsalts stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Ia,where R⁵ is —C(O)NR⁶R⁷ where R⁶ is (C₁-C₆)-alkyl optionally substitutedwith OH, —SH, (C₁-C₄)-alkoxy, (C₁-C₄)-thioalkyl, —F, —Cl, —Br, —I,haloalkyl, —NH₂, —NH(C₁-C₄-alkyl), and —N((C₁-C₄)-alkyl)₂ and R⁷ ishydrogen. In some embodiments, R⁶ is methyl, ethyl, propyl, —CH₂—CH₂—OH,—CH₂—CH₂—NH₂, —CH₂—CH₂—NH(CH₃), —CH₂—CH₂—N(CH₃)₂, —CH₂—CH₂—N(CH₂CH₃)₂and R⁷ is hydrogen and all salts stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Ia,where R⁵ is —C(O)NR⁶R⁷ where R⁶ is (C₁-C₆)-alkyl substituted with anaryl, such as phenyl; and R⁷ is hydrogen. In another embodiment, theinvention embraces compounds of Formula Ia, where R⁵ is —C(O)NR⁶R⁷ whereR⁶ is (C₁-C₆)-alkyl-phenyl such as benzyl and R⁷ is hydrogen.

In another embodiment, the invention embraces compounds of Formula Ia,where R⁵ is —C(O)NR⁶R⁷ where R⁶ is (C₁-C₆)-alkyl substituted with aheterocyclyl, such as piperidine, piperazine, morpholine, imidazoline,pyrimidine, or pyridine; and R⁷ is hydrogen. In another embodiment, theinvention embraces compounds of Formula Ia, where R⁵ is —C(O)NR⁶R⁷ whereR⁶ is (C₁-C₆)-alkyl substituted with a heterocyclyl, such as piperidine,piperazine, morpholine, imidazoline, pyrimidine, or pyridine; and R⁷ is(C₁-C₆)-alkyl. In some embodiments, the heterocyclyl is attached to thecarbon chain at the nitrogen atom of the ring; in other embodiments, theheterocyclyl is attached to the carbon chain at a carbon atom of thering, and all salts stereoisomers, mixtures of stereoisomers, prodrugs,metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Ia,where R⁶ and R⁷ together with the atom to which they are attached form asaturated or unsaturated 3-8 membered ring, such as a 5-6-membered ringfor example pyrrolidine, piperidine, piperazine, or morpholine,optionally substituted with one or more groups independently selectedfrom oxo, —OR¹⁰, —SR¹⁰, —CN, —F, —Cl, —Br, —I, —NR¹⁰R^(10′),(C₁-C₆)-alkyl, aryl-(C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl, and—C(O)—(C₁-C₆)-alkyl; and all salts stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof. Inone embodiment, R⁶ and R⁷ form a piperidine ring optionally substitutedwith OH, oxo, benzyl or acetyl. In one embodiment, R⁶ and R⁷ form apiperazine ring optionally substituted with (C₁-C₆)-alkyl, benzyl oracetyl and all salts stereoisomers, mixtures of stereoisomers, prodrugs,metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Ib:

where,

-   M and M′ are independently selected from hydrogen, —C(O)—R′,    —C(O)—(C₂-C₆)-alkenyl, —C(O)—(C₂-C₆)-alkynyl, —C(O)-aryl,    —C(O)-heterocyclyl, —C(O)O—R′, —C(O)NR′R″, —SO₂OR′,    —SO₂—(C₁-C₆)-alkyl, —SO₂—(C₁-C₆)-haloalkyl, —SO₂-aryl, —SO₂—NR′R″,    —P(O)(OR′)(OR″), and C-linked mono- or di-peptide, where R′ and R″    are independently of each other hydrogen or (C₁-C₆)-alkyl optionally    substituted with one or more substituents independently selected    from —OH, —NH₂, —NH(C₁-C₄)-alkyl, —N((C₁-C₄)-alkyl)₂, —C(O)—OH,    —C(O)—O—(C₁-C₄)-alkyl, and halogen;-   R¹ is (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, heterocyclyl, or aryl, where    the heterocyclyl and the aryl are optionally substituted with one or    more substituents independently selected from —OH, (C₁-C₆)-alkyl,    (C₁-C₆)-alkoxy, hydroxy-(C₁-C₆)alkyl-, alkoxy(C₁-C₆)alkyl-,    —(C₁-C₆)-alkyl —NR¹⁰R^(10′), —NR¹⁰R^(10′), —CO(C₁-C₆)-alkyl,    —C(O)—OH, —C(O)O—(C₁-C₆)-alkyl, —C(O)NR¹⁰R^(10′), —NR¹¹C(O)R¹⁰,    —NR¹¹C(O)NR¹⁰R^(10′), —NR¹¹C(O)OR¹⁰, —SO₂(C₁-C₆)-alkyl,    —SO₂(C₁-C₆)-haloalkyl, —SO₂-aryl, —SO₂NR¹⁰R^(10′), CN, haloalkyl,    and halogen;-   R² is hydrogen, (C₁-C₆)-alkyl, or (C₁-C₆)-alkoxy;-   R³ is unsubstituted (C₁-C₆)-alkyl;-   R⁴ is hydrogen or (C₁-C₆)-alkyl;-   R⁵ is —C(O)—R⁶, —SO₂—R⁶, —C(O)O—R⁶, or —C(O)NR⁶R⁷;-   R⁶ is hydrogen, (C₁-C₆)-alkyl, aryl, or heterocyclyl, where    -   (C₁-C₆)-alkyl is optionally substituted with one or more        substituents independently selected from        -   —OR¹¹, —SR¹¹, —CN, —F, —Cl, —Br, —I, —NR¹⁰R^(10′),            (C₃-C₆)-cycloalkyl, aryl, heterocyclyl, —C(O)—R¹¹,            —C(O)—(C₀-C₆)-alkyl-aryl, —C(O)O—R¹¹,            —C(O)—O—(C₀-C₆)-alkyl-aryl, —C(O)N—R¹⁰R^(10′),            —C(O)NR¹¹—(C₀-C₆)-alkyl-aryl, —NR¹¹C(O)—R¹⁰, and            —NR¹¹C(O)—(C₀-C₆)-alkyl-aryl; wherein the aryl and            heterocyclyl ring substituents may be further substituted            with one or more groups independently selected from            (C₁-C₆)-alkyl, halogen, (C₁-C₆)-haloalkyl, CN, oxo, hydroxy,            (C₁-C₆)-alkoxy, —C(O)—(C₁-C₆)-alkyl, and            —C(O)—O—(C₁-C₆)-alkyl; and where    -   aryl and heterocyclyl are optionally substituted with        (C₁-C₆)-alkyl, halogen, (C₁-C₆)-haloalkyl, CN, oxo, hydroxy,        (C₁-C₆)-alkoxy, —C(O)—(C₁-C₆)-alkyl and —C(O)—O—(C₁-C₆)-alkyl;-   R⁷ is hydrogen or (C₁-C₆)-alkyl; or-   R⁶ and R⁷ together with the atom to which they are attached form a    saturated or unsaturated 3-8 membered ring, optionally incorporating    one or more additional heteroatoms independently selected from one,    two, or three, N, O, or S atoms, and optionally substituted with    oxo, —OH, —SH, —F, —Cl, —Br, —I, —NR¹¹R^(11′), (C₁-C₆)-alkyl,    (C₁-C₆)-alkoxy; (C₁-C₆)-thioalkyl, (C₁-C₆)-haloalkyl;    hydroxy-(C₁-C₆)-alkyl, —C(O)—H, —C(O)—(C₁-C₆)-alkyl, —C(O)OH, or    —C(O)O—(C₁-C₆)-alkyl;-   R¹⁰ and R^(10′) are independently selected from H, (C₁-C₆)-alkyl,    (C₁-C₆)-haloalkyl, aryl, aryl-(C₁-C₆)-alkyl, heteroaryl,    heterocyclyl, —C(O)—H, —C(O)—(C₁-C₆)-alkyl, —C(O)-aryl, and    —C(O)—(C₁-C₆)-alkyl-aryl; or-   R¹⁰ and R^(10′) together with the atom to which they are attached    form a saturated or unsaturated 3-8 membered ring, optionally    incorporating one or more additional heteroatoms independently    selected from one, two, or three, N, O, or S atoms, and optionally    substituted with one or more substituents independently selected    from oxo, —OH, —F, —Cl, —Br, —I, —NR¹¹R^(11′), (C₁-C₆)-alkyl,    (C₁-C₆)-alkoxy; (C₁-C₆)-haloalkyl; hydroxy-(C₁-C₆)-alkyl, —C(O)—H,    —C(O)—(C₁-C₆)-alkyl, —C(O)OH, and —C(O)—O—(C₁-C₆)-alkyl;-   R¹¹ and R^(11′) are independently selected from hydrogen and    (C₁-C₆)-alkyl; and-   A is (C₁-C₄)-alkylene, (C₂-C₄)-alkenylene, or (C₂-C₄)-alkynylene;    and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Ib,where A is (C₁-C₄)-alkylene; for example —CH₂—CH₂— or —CH₂—CH₂—CH₂—; andM and M′ are hydrogen and all salts, stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof

In another embodiment, the invention embraces compounds of Formula Ib,where R¹, R² and R³ are independently selected from methyl, ethyl,n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl,cyclobutyl, cyclopropyl-methyl, methyl-cyclopropyl, pentyl where thepoint of attachment of the pentyl group to the remainder of the moleculecan be at any location on the pentyl fragment, cyclopentyl, hexyl wherethe point of attachment of the hexyl group to the remainder of themolecule can be at any location on the hexyl fragment, and cyclohexyl;and M and M′ are hydrogen; and all salts, stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Ib,where R¹ is optionally substituted aryl, R² and R³ are independently(C₁-C₆)-alkyl; and M and M′ are hydrogen. In some embodiments, R¹ isunsubstituted phenyl. In another embodiment, the invention embracescompounds of Formula Ib, where R¹ is phenyl substituted with one or moresubstituents selected from (C₁-C₄)-alkyl, halogen, (C₁-C₄)-haloalkyl-,hydroxy, (C₁-C₄)-alkoxy, and —CO(C₁-C₄)-alkyl; and M and M′ arehydrogen; and all salts stereoisomers, mixtures of stereoisomers,prodrugs, metabolites, solvates, and hydrates thereof. In anotherembodiment, the invention embraces compounds of Formula Ib, where R¹ isphenyl substituted with one or more substituents independently selectedfrom (C₁-C₆)-alkyl, such as methyl; halogen, such as fluoro or chloro;and (C₁-C₆)-haloalkyl, such as CF₃ or CHF₂; and M and M′ are hydrogen;and all salts stereoisomers, mixtures of stereoisomers, prodrugs,metabolites, solvates, and hydrates thereof. In some of the priorembodiments, the phenyl substitution is at the para position. In someembodiments, the invention embraces compounds of Formula Ia, where R²and R³ are methyl; and M and M′ are hydrogen; and all salts,stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Ib,where R¹ and R² are independently (C₁-C₆)-alkoxy, R³ is unsubstituted(C₁-C₆)-alkyl; and M and M′ are hydrogen; in some embodiments, R¹ is(C₁-C₆)-alkoxy; R² and R³ are independently (C₁-C₆)-alkyl, and M and M′are hydrogen, and in yet another embodiment, R² is (C₁-C₆)-alkoxy; R¹and R³ are independently (C₁-C₆)-alkyl and M and M′ are hydrogen; andall salts, stereoisomers, mixtures of stereoisomers, prodrugs,metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Ib,where R⁵ is selected from —C(O)—(C₁-C₆)-alkyl and —S(O)₂—(C₁-C₆)-alkylwhere the alkyl is optionally substituted with OH, —SH, (C₁-C₄)-alkoxy,(C₁-C₄)-thioalkyl, —CN, —F, —Cl, —Br, —I, —NH₂, —NH(C₁-C₄)-alkyl, or—N((C₁-C₄)-alkyl)₂, and M and M′ are hydrogen; and in some embodiments,R⁵ is selected from —C(O)—CH₂—CH₃, —C(O)—CH₂—CH₂—CH₃, —C(O)—CH₂—CH₂—OH,—C(O)—CH₂—CH₂—NH₂, —C(O)—CH₂—CH₂—NH(CH₃), —C(O)—CH₂—CH₂—N(CH₃)₂, and—C(O)—CH₂—CH₂—N(CH₂CH₃)₂; and M and M′ are hydrogen; and all saltsstereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Ibwhere R⁵ is selected from —C(O)—(C₁-C₆)-alkyl-aryl and—S(O)₂—(C₁-C₆)-alkyl-aryl, where the aryl group is optionallysubstituted with one or more groups independently selected from(C₁-C₄)-alkyl, OH, —SH, (C₁-C₄)-alkoxy, (C₁-C₄)-thioalkyl, —F, —Cl, —Br,—I, haloalkyl, —NH₂, —NH(C₁-C₄)-alkyl, and —N((C₁-C₄)-alkyl)₂, forexample compounds where R⁵ is benzyl optionally substituted with one ormore groups independently selected from methyl, chloro, fluoro, andtrifluoromethyl; and M and M′ are hydrogen.

In another embodiment, the invention embraces compounds of Formula Ib,where R⁵ is —C(O)-aryl or —S(O)₂-aryl where the aryl is optionallysubstituted with one or more groups independently selected from(C₁-C₄)-alkyl, OH, —SH, (C₁-C₄)-alkoxy, (C₁-C₄)-thioalkyl, —F, —Cl, —Br,—I, haloalkyl, CN, —NH₂, —NH(C₁-C₄)-alkyl, and —N((C₁-C₄)-alkyl)₂, forexample where R⁵ is —C(O)phenyl optionally substituted with one or moresubstituents independently selected from fluoro, chloro, ortrifluoromethyl, and M and M′ are hydrogen; and all salts stereoisomers,mixtures of stereoisomers, prodrugs, metabolites, solvates, and hydratesthereof.

In another embodiment, the invention embraces compounds of Formula Ib,where R⁵ is —C(O)OR⁶; and in some embodiments, R⁵ is—C(O)O—(C₁-C₆)-alkyl, —C(O)O—(C₁-C₆)-alkyl-phenyl, or —C(O)O-phenyloptionally substituted with one or more groups independently selectedfrom (C₁-C₆)-alkyl, OR¹⁰, —SR¹⁰, —CN, —F, —Cl, —Br, —I, CN, haloalkyl,and —NR¹⁰R^(10′), and M and M′ are hydrogen; and all saltsstereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Ib,where R⁵ is —C(O)NR⁶R⁷ where R⁶ and R⁷ are hydrogen, and M and M′ arehydrogen; and all salts stereoisomers, mixtures of stereoisomers,prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Ib,where R⁵ is —C(O)NR⁶R⁷ where R⁶ is (C₁-C₆)-alkyl optionally substitutedwith —OR¹⁰, —SR¹⁰, —CN, —F, —Cl, —Br, —I, or —NR¹⁰R^(10′) and R⁷ is(C₁-C₆)-alkyl; and M and M′ are hydrogen. In some embodiments, R⁶ and R⁷are independently selected from methyl, ethyl, propyl, and butyl, and Mand M′ are hydrogen; and all salts stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Ib,where R⁵ is —C(O)NR⁶R⁷ where R⁶ is (C₁-C₆)-alkyl optionally substitutedwith OH, —SH, (C₁-C₄)-alkoxy, (C₁-C₄)-thioalkyl, —F, —Cl, —Br, —I,haloalkyl, —NH₂, —NH(C₁-C₄-alkyl), and —N((C₁-C₄)-alkyl)₂, R⁷ ishydrogen; and M and M′ are hydrogen. In some embodiments, R⁶ is methyl,ethyl, propyl, —CH₂—CH₂—OH, —CH₂—CH₂—NH₂, —CH₂—CH₂—NH(CH₃),—CH₂—CH₂—N(CH₃)₂ or —CH₂—CH₂—N(CH₂CH₃)₂; R⁷ is hydrogen and M and M′ arehydrogen; and all salts stereoisomers, mixtures of stereoisomers,prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Ib,where R⁵ is —C(O)NR⁶R⁷ where R⁶ is (C₁-C₆)-alkyl substituted with aheterocyclyl, such as piperidine, piperazine, morpholine, imidazoline,pyrimidine, or pyridine; R⁷ is hydrogen, and M and M′ are hydrogen. Inanother embodiment, the invention embraces compounds of Formula Ib,where R⁵ is —C(O)NR⁶R⁷ where R⁶ is (C₁-C₆)-alkyl substituted with aheterocyclyl, such as pyrrolidine, piperidine, piperazine, morpholine,imidazoline, pyrimidine, or pyridine; R⁷ is (C₁-C₆)-alkyl; and M and M′are hydrogen. In some embodiments, the heterocyclyl is attached to thecarbon chain at the nitrogen atom of the ring; in other embodiments, theheterocyclyl is attached to the carbon chain at a carbon atom of thering and all salts stereoisomers, mixtures of stereoisomers, prodrugs,metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula Ib,where R⁶ and R⁷ together with the atom to which they are attached form asaturated or unsaturated 3-8 membered ring, such as a 5-6-membered ringsuch as pyrrolidine, piperidine, piperazine, or morpholine, optionallysubstituted with one or more groups independently selected from oxo,—OR¹⁰, —SR¹⁰, —CN, —F, —Cl, —Br, —I, —NR¹⁰R^(10′), (C₁-C₆)-alkyl,aryl-(C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl, and —C(O)—(C₁-C₆)-alkyl, and Mand M′ are hydrogen; and all salts stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof. Inone embodiment, R⁶ and R⁷ form a piperidine ring optionally substitutedwith OH, oxo, benzyl or acetyl, and M and M′ are hydrogen. In oneembodiment, R⁶ and R⁷ form a piperazine ring optionally substituted with(C₁-C₆)-alkyl, benzyl or acetyl, and M and M′ are hydrogen; and allsalts stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces a method of treating orsuppressing an oxidative stress disorder selected from a mitochondrialdisorder, an impaired energy processing disorder, a neurodegenerativedisorder and a disease of aging, modulating one or more energybiomarkers, normalizing one or more energy biomarkers, or enhancing oneor more energy biomarkers, by administering a therapeutically effectiveamount of one or more compounds of Formula I, Formula Ia, or Formula Ib;and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces a method of treating orsuppressing an oxidative stress disorder selected from a mitochondrialdisorder, an impaired energy processing disorder, a neurodegenerativedisorder and a disease of aging, modulating one or more energybiomarkers, normalizing one or more energy biomarkers, or enhancing oneor more energy biomarkers, by administering a therapeutically effectiveamount of one or more compounds of Formula I, where R¹, R² and R³ areindependently selected from (C₁-C₄)-alkyl; A is —CH₂—CH₂—, R⁴ ishydrogen, R⁵ is —C(O)—R⁶, —SO₂—R⁶, —C(O)O—R⁶, or —C(O)NR⁶R⁷; and allsalts, stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces a method of an oxidativestress disorder selected from a mitochondrial disorder, an impairedenergy processing disorder, a neurodegenerative disorder and a diseaseof aging, modulating one or more energy biomarkers, normalizing one ormore energy biomarkers, or enhancing one or more energy biomarkers, byadministering a therapeutically effective amount of one or morecompounds of Formula Ia, where R¹, R² and R³ are independently selectedfrom (C₁-C₄)-alkyl; A is —CH₂—CH₂—, R⁴ is hydrogen, R⁵ is —C(O)—R⁶,—SO₂—R⁶, —C(O)O—R⁶, or —C(O)NR⁶R⁷; and all salts, stereoisomers,mixtures of stereoisomers, prodrugs, metabolites, solvates, and hydratesthereof.

In another embodiment, the invention embraces a method of treating orsuppressing an oxidative stress disorder selected from a mitochondrialdisorder, an impaired energy processing disorder, a neurodegenerativedisorder and a disease of aging, modulating one or more energybiomarkers, normalizing one or more energy biomarkers, or enhancing oneor more energy biomarkers, by administering a therapeutically effectiveamount of one or more compounds of Formula Ib, where M and M′ areindependently selected from hydrogen; R¹, R² and R³ are independentlyselected from (C₁-C₄)-alkyl; A is —CH₂—CH₂—; R⁴ is hydrogen; R⁵ is—C(O)—R⁶, —SO₂—R⁶, —C(O)O—R⁶, or —C(O)NR⁶R⁷; and all salts,stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula I,selected from:

-   1-ethyl-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(2-hydroxyethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(2-(dimethylamino)ethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)methanesulfonamide;-   4-fluoro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzenesulfonamide;-   3-(2-(dimethylamino)ethyl)-1-methyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   3-ethyl-1-methyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   N-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-4-fluorobenzenesulfonamide;-   1-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-methyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-3-ethylurea;-   N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   4-methoxy-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzenesulfonamide;-   1-(2-morpholinoethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   ethyl    2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethylcarbamate;-   4-benzyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;-   4-hydroxy-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;-   N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;-   1,1-diethyl-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(4-chlorobenzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   4-methyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;-   4-acetyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;-   4-oxo-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;-   N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)nicotinamide;-   4-chloro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   4-fluoro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   4-(trifluoromethyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   2-(4-chlorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   2-(4-fluorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   1-(4-fluorobenzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   N-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-4,4-difluorocyclohexanecarboxamide;-   2-(4-chlorophenyl)-N-methyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   2-(4-methoxyphenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   4-acetyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   4-methyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   4-cyano-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   1-phenyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)cyclopropanecarboxamide;-   1-(4-methoxyphenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)cyclopropanecarboxamide;-   2-(4-methoxyphenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   2-(naphthalen-1-yl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   2-(2-methoxyphenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   3-(4-fluorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)propanamide;-   2-hydroxy-2-phenyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   2-(4-chlorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)propanamide;-   2-(4-fluorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)propanamide;-   4-fluoro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;-   4,4-difluoro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;-   2-hydroxy-2-(4-(trifluoromethyl)phenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   1-(4-chlorobenzyl)-1-methyl-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   2-(4-chlorophenyl)-2-hydroxy-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   1-(pyridin-2-ylmethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(pyridin-4-ylmethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   3-ethyl-1-methyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(pyridin-3-ylmethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;    and-   1-(4-(trifluoromethyl)benzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;    and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates, and hydrates thereof.

In one embodiment, the invention embraces compounds of Formula II:

where,

-   R is selected from the group consisting of:

where the * indicates the point of attachment of R to the remainder ofthe molecule;

-   M and M′ are independently selected from hydrogen, —C(O)—R′,    —C(O)—(C₂-C₆)-alkenyl, —C(O)—(C₂-C₆)-alkynyl, —C(O)-aryl,    —C(O)-heterocyclyl, —C(O)O—R′, —C(O)NR′R″, —SO₂OR′,    —SO₂—(C₁-C₆)-alkyl, —SO₂—(C₁-C₆)-haloalkyl, —SO₂-aryl, —SO₂—NR′R″,    —P(O)(OR′)(OR″), and C-linked mono- or di-peptide, where R′ and R″    are independently of each other hydrogen or (C₁-C₆)-alkyl optionally    substituted with one or more substituents independently selected    from —OH, —NH₂, —NH(C₁-C₄)-alkyl, —N((C₁-C₄)-alkyl)₂, —C(O)—OH,    —C(O)—O—(C₁-C₄)-alkyl, and halogen;-   R¹ is independently selected from hydrogen and (C₁-C₆)-alkyl;-   R² is independently selected from (C₁-C₆)-alkyl;-   R³⁰ is (C₁-C₆)-alkyl, aryl, or heterocyclyl, where the alkyl, aryl,    and heterocyclyl are optionally substituted with one or more    substituents independently selected from —OH, (C₁-C₄)-alkoxy, —NH₂,    —NH(C₁-C₄)-alkyl, —N((C₁-C₄)-alkyl)₂, —C(O)—OH,    —C(O)—O—(C₁-C₄)-alkyl, and halogen;-   A is (C₁-C₄)-alkylene, (C₂-C₄)-alkenylene, or (C₂-C₄)-alkynylene;-   B is selected from —C(O)NR⁴—, —NR⁴C(O)—, —NR⁴C(O)NR⁴—, —NR⁴SO₂—, and    —SO₂NR⁴—;-   R⁴ is hydrogen or (C₁-C₆)-alkyl;    and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces a method of treating orsuppressing a mitochondrial disorder, modulating one or more energybiomarkers, normalizing one or more energy biomarkers, or enhancing oneor more energy biomarkers, by administering a therapeutically effectiveamount or effective amount of one or more compounds of formula II asdescribed above.

In another embodiment, the invention embraces compounds of Formula IIa:

where,

-   R¹ is independently selected from hydrogen and (C₁-C₆)-alkyl;-   R² is independently selected from (C₁-C₆)-alkyl;-   R³⁰ is (C₁-C₆)-alkyl, aryl, or heterocyclyl, where the alkyl, aryl,    and heterocyclyl are optionally substituted with one or more    substituents independently selected from —OH, (C₁-C₄)-alkoxy, —NH₂,    —NH(C₁-C₄)-alkyl, —N((C₁-C₄)-alkyl)₂, —C(O)—OH,    —C(O)—O—(C₁-C₄)-alkyl, aryl, heterocyclyl, and halogen;-   A is (C₁-C₄)-alkylene, (C₂-C₄)-alkenylene, or (C₂-C₄)-alkynylene;-   B is selected from —C(O)NR⁴—, —NR⁴C(O)—, —NR⁴C(O)NR⁴—, —NR⁴SO₂—, and    —SO₂NR⁴—; and-   R⁴ is hydrogen or (C₁-C₆)-alkyl;    and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula IIa,where R¹ and R² are independently selected from methyl, ethyl, n-propyl,isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl,cyclobutyl, cyclopropyl-methyl, methyl-cyclopropyl, pentyl where thepoint of attachment of the pentyl group to the remainder of the moleculecan be at any location on the pentyl fragment, cyclopentyl, hexyl wherethe point of attachment of the hexyl group to the remainder of themolecule can be at any location on the hexyl fragment, and cyclohexyl;and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula IIa,where one of R¹ and R³ is methyl, and R² is hydrogen. In anotherembodiment the invention embraces compounds of Formula IIa, where R¹ andR² are methyl; and all salts, stereoisomers, mixtures of stereoisomers,prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula IIa,where B is —NR⁴C(O)—, —NR⁴S(O)₂—, and —NR⁴C(O)NR⁴—, and in someembodiments, B is —NHC(O)—, —NHS(O)₂—, and —NHC(O)NR⁴— and all saltsstereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof. In another embodiment, the inventionembraces compounds of Formula IIa, where B is —NR⁴C(O)—; and in someembodiments, B is —NHC(O)—; and all salts stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof. Inanother embodiment, the invention embraces compounds of Formula IIa,where B is —NR⁴S(O)₂—; and in some embodiments, B is —NHS(O)₂—; and allsalts stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof. In yet another embodiment, the inventionembraces compounds of Formula IIa, where B is —NR⁴C(O)NR⁴—; and in someembodiments, B is —NHC(O)NH—; and all salts stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof.

In some of the prior embodiments, the invention embraces compounds ofFormula IIa, where R³⁰ is optionally substituted (C₁-C₆)-alkyl oroptionally substituted aryl, and all salts stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof. Insome embodiments, the invention embraces compounds of Formula IIa, whereR³⁰ is aryl, and all salts stereoisomers, mixtures of stereoisomers,prodrugs, metabolites, solvates, and hydrates thereof. In otherembodiments, the invention embraces compounds of Formula IIa, where R³⁰is unsubstituted phenyl, and all salts stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof. Inanother embodiment, the invention embraces compounds of Formula IIa,where R³⁰ is phenyl substituted with one or more substituentsindependently selected from (C₁-C₆)-alkyl, halogen, (C₁-C₆)-haloalkyl-,hydroxy, (C₁-C₆)-alkoxy, CN, nitro, —COOR⁴, —NR⁵R⁶, —CONR⁵R⁶, and —COR⁴;and all salts stereoisomers, mixtures of stereoisomers, prodrugs,metabolites, solvates, and hydrates thereof. In another embodiment, theinvention embraces compounds of Formula IIa, where R³⁰ is phenylsubstituted with one or two substituents independently selected from(C₁-C₆)-alkyl, halogen, and (C₁-C₆)-haloalkyl-, and all saltsstereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof. In another embodiment, the inventionembraces compounds of Formula IIa, where R³⁰ is phenyl substituted with(C₁-C₆)-alkyl such as methyl; halogen, such as fluoro or chloro; or(C₁-C₆)-haloalkyl, such as CF₃ or CHF₂; and all salts stereoisomers,mixtures of stereoisomers, prodrugs, metabolites, solvates, and hydratesthereof. In some of the prior embodiments, the phenyl substitution is atthe para position.

In another embodiment, the invention embraces compounds of Formula IIa,where R³⁰ is an optionally substituted (C₁-C₆)-alkyl, and all saltsstereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof. In another embodiment, the inventionembraces compounds of Formula IIa, where R³⁰ is (C₁-C₆)-alkylsubstituted with heterocyclyl, and in yet some other embodiments, R³⁰ is(C₁-C₆)-alkyl substituted with 1,2-dithiolan-3-yl; and all saltsstereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula IIb:

where,

-   R¹ is independently selected from hydrogen and (C₁-C₆)-alkyl;-   R² is independently selected from (C₁-C₆)-alkyl;-   R³⁰ is (C₁-C₆)-alkyl, aryl, or heterocyclyl, where the alkyl, aryl,    and heterocyclyl are optionally substituted with one or more    substituents independently selected from —OH, (C₁-C₄)-alkoxy, —NH₂,    —NH(C₁-C₄)-alkyl, —N((C₁-C₄)-alkyl)₂, —C(O)—OH,    —C(O)—O—(C₁-C₄)-alkyl, and halogen;-   A is (C₁-C₄)-alkylene, (C₂-C₄)-alkenylene, or (C₂-C₄)-alkynylene;-   B is selected from —C(O)NR⁴—, —NR⁴C(O)—, —NR⁴C(O)NR⁴—, —NR⁴SO₂—, and    —SO₂NR⁴—;-   R⁴ is hydrogen or (C₁-C₆)-alkyl;-   M and M′ are independently selected from hydrogen, —C(O)—R′,    —C(O)—(C₂-C₆)-alkenyl,    -   —C(O)—(C₂-C₆)-alkynyl, —C(O)-aryl, —C(O)-heterocyclyl,        —C(O)O—R′, —C(O)NR′R″, —SO₂OR′, —SO₂—(C₁-C₆)-alkyl,        —SO₂—(C₁-C₆)-haloalkyl, —SO₂-aryl, —SO₂—NR′R″, —P(O)(OR′)(OR″),        and C-linked mono- or di-peptide, where R′ and R″ are        independently of each other hydrogen or (C₁-C₆)-alkyl optionally        substituted with one or more substituents independently selected        from —OH, —NH₂, —NH(C₁-C₄)-alkyl, —N((C₁-C₄)-alkyl)₂, —C(O)—OH,        —C(O)—O—(C₁-C₄)-alkyl, and halogen;        and all salts, stereoisomers, mixtures of stereoisomers,        prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula IIb,where R¹ and R² are independently selected from methyl, ethyl, n-propyl,isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl,cyclobutyl, cyclopropyl-methyl, methyl-cyclopropyl, pentyl where thepoint of attachment of the pentyl group to the remainder of the moleculecan be at any location on the pentyl fragment, cyclopentyl, hexyl wherethe point of attachment of the hexyl group to the remainder of themolecule can be at any location on the hexyl fragment and cyclohexyl,and M and M′ are hydrogen; and all salts, stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula IIb,where one of R¹ and R³ is methyl, and R² is hydrogen. In anotherembodiment, the invention embraces compounds of Formula IIb, where R¹and R² are methyl, and M and M′ are hydrogen and all salts,stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula IIb,where B is —NR⁴C(O)—; and in some embodiments, B is —NHC(O)—; and M andM′ are hydrogen; and all salts, stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof. Inanother embodiment, the invention embraces compounds of Formula IIb,where B is —NR⁴S(O)₂—; and in some embodiments, B is —NHS(O)₂—, and Mand M′ are hydrogen; and all salts, stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof. Inyet another embodiment, the invention embraces compounds of Formula IIb,where B is —NR⁴C(O)NR⁴—; and in some embodiments, B is —NHC(O)NH—; and Mand M′ are hydrogen; and all salts, stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof.

In some of the prior embodiments, the invention embraces compounds ofFormula IIb, where R³⁰ is optionally substituted (C₁-C₆)-alkyl oroptionally substituted aryl, and M and M′ are hydrogen; and all salts,stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof. In some embodiments, the inventionembraces compounds of Formula IIb, where R³⁰ is aryl, and M and M′ arehydrogen; and all salts, stereoisomers, mixtures of stereoisomers,prodrugs, metabolites, solvates, and hydrates thereof. In otherembodiments, the invention embraces compounds of Formula IIb, where R³⁰is unsubstituted phenyl, and M and M′ are hydrogen; and all salts,stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof. In another embodiment, the inventionembraces compounds of Formula IIb, where R³⁰ is phenyl substituted withone or more substituents independently selected from (C₁-C₆)-alkyl,halogen, (C₁-C₆)-haloalkyl, hydroxy, (C₁-C₆)-alkoxy, CN, nitro, —COOR⁴,—NR⁵R⁶, —CONR⁵R⁶, and —COR⁴, and M and M′ are hydrogen; and all salts,stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof. In another embodiment, the inventionembraces compounds of Formula IIb, where R³⁰ is phenyl substituted withone or two substituents independently selected from (C₁-C₆)-alkyl,halogen, and (C₁-C₆)-haloalkyl, and M and M′ are hydrogen; and allsalts, stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof. In another embodiment, the inventionembraces compounds of Formula IIb, where R³⁰ is phenyl substituted with(C₁-C₆)-alkyl, such as methyl; halogen, such as fluoro or chloro; or(C₁-C₆)-haloalkyl, such as CF₃ or CHF₂; and M and M′ are hydrogen; andall salts, stereoisomers, mixtures of stereoisomers, prodrugs,metabolites, solvates, and hydrates thereof. In some of the priorembodiments, the phenyl substitution is at the para position.

In another embodiment, the invention embraces compounds of Formula IIb,where R³⁰ is an optionally substituted (C₁-C₆)-alkyl, and M and M′ arehydrogen; and all salts, stereoisomers, mixtures of stereoisomers,prodrugs, metabolites, solvates, and hydrates thereof. In anotherembodiment, the invention embraces compounds of Formula IIb, where R³⁰is (C₁-C₆)-alkyl substituted with heterocyclyl, and in yet some otherembodiments, R³⁰ is (C₁-C₆)-alkyl substituted with 1,2-dithiolan-3-yl,and M and M′ are hydrogen; and all salts stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces a method of treating orsuppressing an oxidative stress disorder selected from a mitochondrialdisorder, an impaired energy processing disorder, a neurodegenerativedisorder and a disease of aging, modulating one or more energybiomarkers, normalizing one or more energy biomarkers, or enhancing oneor more energy biomarkers, by administering a therapeutically effectiveamount of one or more compounds of Formula II, Formula IIa, or FormulaIIb; and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces a method of treating orsuppressing an oxidative stress disorder selected from a mitochondrialdisorder, an impaired energy processing disorder, a neurodegenerativedisorder and a disease of aging, modulating one or more energybiomarkers, normalizing one or more energy biomarkers, or enhancing oneor more energy biomarkers, by administering a therapeutically effectiveamount of one or more compounds of Formula IIa, where R¹ and R² areindependently selected from (C₁-C₄)-alkyl; A is —CH₂—CH₂—; B is—NR⁴C(O)—, —NR⁴C(O)NR⁴—, or —NR⁴SO₂—; and R³⁰ is optionally substitutedalkyl or optionally substituted phenyl; and all salts, stereoisomers,mixtures of stereoisomers, prodrugs, metabolites, solvates, and hydratesthereof.

In another embodiment, the invention embraces a method of treating orsuppressing an oxidative stress disorder selected from a mitochondrialdisorder, an impaired energy processing disorder, a neurodegenerativedisorder and a disease of aging, modulating one or more energybiomarkers, normalizing one or more energy biomarkers, or enhancing oneor more energy biomarkers, by administering a therapeutically effectiveamount of one or more compounds of Formula IIa, where R¹ and R² areindependently selected from (C₁-C₄)-alkyl; A is —CH₂—CH₂—; B is—NR⁴C(O)—, —NR⁴C(O)NR⁴—, or —NR⁴SO₂—; and R³⁰ is optionally substitutedalkyl or phenyl, and all salts, stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces a method of treating orsuppressing an oxidative stress disorder selected from a mitochondrialdisorder, an impaired energy processing disorder, a neurodegenerativedisorder and a disease of aging, modulating one or more energybiomarkers, normalizing one or more energy biomarkers, or enhancing oneor more energy biomarkers, by administering a therapeutically effectiveamount of one or more compounds of Formula IIb, where M and M′ areindependently selected from hydrogen, R¹ and R² are independentlyselected from (C₁-C₄)-alkyl; A is —CH₂—CH₂—; B is —NR⁴C(O)—,—NR⁴C(O)NR⁴—, or —NR⁴SO₂—; and R³⁰ is optionally substituted alkyl oroptionally substituted phenyl; and all salts, stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces a method of treating orsuppressing an oxidative stress disorder selected from a mitochondrialdisorder, an impaired energy processing disorder, a neurodegenerativedisorder and a disease of aging, modulating one or more energybiomarkers, normalizing one or more energy biomarkers, or enhancing oneor more energy biomarkers, by administering a therapeutically effectiveamount or effective amount of one or more compounds of Formula IIb,where and M and M′ are hydrogen, R¹ and R² are independently selectedfrom (C₁-C₄)-alkyl; A is —CH₂—CH₂—; B is —NR⁴C(O)—, —NR⁴C(O)NR⁴—, or—NR⁴SO₂—; and R³⁰ is optionally substituted alkyl or optionallysubstituted phenyl, and all salts, stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula II,selected from:

-   N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-4-methylbenzenesulfonamide;-   N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)methanesulfonamide;-   N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   1-ethyl-3-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   5-(1,2-dithiolan-3-yl)-N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)pentanamide;    and-   N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)hexanamide;    and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of Formula III

where R is selected from the group consisting of:

where the * indicates the point of attachment of R to the remainder ofthe molecule;

-   A is (C₁-C₄)-alkylene, (C₂-C₄)-alkenylene, or (C₂-C₄)-alkynylene;-   B³ is C(O) or S(O)₂;-   R¹ is independently selected from (C₁-C₆)-alkyl and (C₁-C₆)-alkoxy;-   R² is independently selected from hydrogen, (C₁-C₆)-alkyl, and    (C₁-C₆)-alkoxy;-   R³ is (C₁-C₆)-alkyl;-   R³⁵ and R³⁶ are independently selected from hydrogen, hydroxy,    alkoxy, (C₁-C₄₀)-alkyl, (C₂-C₄₀)-alkenyl, (C₂-C₄₀)-alkynyl, aryl or    heterocyclyl;-   where the alkyl, alkenyl or alkynyl groups may optionally be    substituted with —OR¹⁰, —SR¹⁰, —CN, —F, —Cl, —Br, —I,    —NR^(10a)R^(10b), oxo, (C₃-C₆)-cycloalkyl, aryl, aryl-(C₁-C₆)-alkyl,    heteroaryl, heterocyclyl, —C(O)—R¹¹, —C(O)—(C₀-C₆)-alkyl-aryl,    —C(O)—O—R¹¹, —C(O)—O—(C₀-C₆)-alkyl-aryl, —C(O)—N—R^(11a)R^(11b),    —C(O)—N—(C₀-C₆)-alkyl-aryl, —N—C(O)—R¹¹, —N—C(O)—(C₀-C₆)-alkyl-aryl;    and-   where the aryl, heteroaryl and heterocyclyl rings may be further    substituted with (C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl, —CN, —F, —Cl,    —Br, —I, —NR^(10a)R^(10b), oxo, hydroxy, (C₁-C₆)-alkoxy,    —C(O)—(C₁-C₆)-alkyl and —C(O)—O—(C₁-C₆)-alkyl; and-   where one of the carbons of the alkyl, alkenyl, or alkynyl groups    may be replaced by a heteroatom selected from O, N or S; or-   R³⁵ and R³⁶ together with the atom to which they are attached form a    saturated or unsaturated 3-8 membered ring, optionally incorporating    one or more additional heteroatoms independently selected from one,    two, or three, N, O, or S atoms, and optionally substituted with    oxo, —OR¹⁰, —SR¹⁰, —CN, —F, —Cl, —Br, —I, —NR^(10a)R^(10b),    (C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl; hydroxy-(C₁-C₆)-alkyl, —C(O)—H,    —C(O)—(C₁-C₆)-alkyl, —C(O)—OH, or —C(O)—O—(C₁-C₆)-alkyl;-   R¹⁰, R^(10a), and R^(10b) are independently selected from the group    consisting of H, (C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl, aryl,    aryl-(C₁-C₆)-alkyl, heteroaryl, heterocyclyl, —C(O)—H,    —C(O)—(C₁-C₆)-alkyl, —C(O)-aryl and —C(O)—(C₁-C₆)-alkyl-aryl;-   R¹¹, R^(11a), and R^(11b) are selected from hydrogen and    (C₁-C₆)-alkyl; or R^(11a) and R^(11b) together with the atom to    which they are attached form a saturated or unsaturated 3-8 membered    ring, optionally incorporating one or more additional heteroatoms    independently selected from one, two, or three, N, O, or S atoms,    and optionally substituted with oxo, —OR¹⁰, —SR¹⁰, —CN, —F, —Cl,    —Br, —I, —NR^(10a)R^(10b), (C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl;    hydroxy-(C₁-C₆)-alkyl, —C(O)—H, —C(O)—(C₁-C₆)-alkyl, —C(O)—OH, or    —C(O)—O—(C₁-C₆)-alkyl; and-   M and M′ are independently selected from hydrogen, —C(O)—R¹²,    —C(O)—(C₂-C₆)-alkenyl, —C(O)—(C₂-C₆)-alkynyl, —C(O)-aryl;    —C(O)-heteroaryl, —C(O)O—R¹², —C(O)NR^(12a)R^(12b), —SO₂OR¹²,    —SO₂—(C₁-C₆)-alkyl, —SO₂—(C₁-C₆)-haloalkyl; —SO₂-aryl,    —SO₂—NR^(12a)R^(12b), —P(O)(OR^(12a))(OR^(12b)), and C-linked mono    or di-peptide, where R¹², R^(12a), and R^(12b) are hydrogen or    (C₁-C₆)-alkyl optionally substituted with —OH, —NH₂,    —NH(C₁-C₄)-alkyl, —N ((C₁-C₄)-alkyl)₂, —C(O)—OH,    —C(O)—O—(C₁-C₄)-alkyl or halogen;    and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates, and hydrates thereof.

In some embodiments, the invention embraces compounds of Formula III,wherein the following compounds are excluded:

-   N-(4-(1H-imidazol-1-yl)phenyl)-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)propanamide;    N-(2-(4-decylpiperazin-1-yl)-1-phenylethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    N-(2-(4-(10-hydroxydecyl)piperazin-1-yl)-1-phenylethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    N-(2-(4-(10-hydroxydecyl)piperazin-1-yl)-2-oxo-1-phenylethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    N-(4-hydroxy-3,5-dimethylphenyl)-5-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)pentanamide;    5-(2,5-dihydroxy-3,4,6-trimethylphenyl)-N-(4-hydroxy-3,5-dimethylphenyl)pentanamide;    4,5-dimethoxy-2-methyl-3,6-dioxo-N-phenethylcyclohexa-1,4-dienecarboxamide;    4,5-dimethoxy-2-methyl-3,6-dioxo-N-phenylcyclohexa-1,4-dienecarboxamide;    N-(4-(4-tert-butylphenoxy)phenyl)-2-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dienyl)-N-methylacetamide;    1-(3-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dienyl)propanoyl)pyrrolidine-2-carboxylic    acid;    2-(3-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dienyl)propanamido)-3-(4-hydroxyphenyl)propanoic    acid;    2-(3-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dienyl)propanamido)pentanedioic    acid;    2-(3-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dienyl)propanamido)propanoic    acid; or    2-(3-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dienyl)propanamido)acetic    acid.

In another embodiment, the invention embraces compounds of formula IIIa:

where:

-   A is (C₁-C₄)-alkylene, (C₂-C₄)-alkenylene, or (C₂-C₄)-alkynylene;-   B is —C(O)NR⁴— or —S(O)₂NR⁴—;-   R¹, R², and R³ are independently unsubstituted (C₁-C₆)-alkyl;-   R⁴ is hydrogen or (C₁-C₆)-alkyl;-   R³⁰ is hydrogen, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,    aryl, or heterocyclyl,    -   where the alkyl, alkenyl or alkynyl groups may optionally be        substituted with —OR¹⁰, —SR¹⁰, —CN, —F, —Cl, —Br, —I,        —NR¹⁰R^(10′), oxo, (C₃-C₆)-cycloalkyl, aryl, aryl-(C₁-C₆)-alkyl,        heteroaryl, heterocyclyl, —C(O)—R¹¹, —C(O)—C₀-C₆-alkyl-aryl,        —C(O)—O—R¹¹, —C(O)—O—(C₀-C₆)-alkyl-aryl, —C(O)—N—R¹¹R^(11′),        —C(O)—N—(C₀-C₆)-alkyl-aryl, —N—C(O)—R¹¹,        —N—C(O)—(C₀-C₆)-alkyl-aryl; or where one of the carbons of the        alkyl, alkenyl, or alkynyl groups may be replaced by a        heteroatom selected from O, N or S; and    -   where the aryl, heteroaryl and heterocyclyl rings may be further        substituted with (C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl, —CN, —F, —Cl,        —Br, —I, —NR¹⁰R^(10′), oxo, hydroxy, (C₁-C₆)-alkoxy,        —C(O)—(C₁-C₆)-alkyl and —C(O)—O—(C₁-C₆)-alkyl; or-   R³⁰ and R⁴ together with the atom to which they are attached form a    saturated or unsaturated 3-8 membered ring, optionally incorporating    one or more additional heteroatoms independently selected from one,    two, or three, N, O, or S atoms, and optionally substituted with    oxo, —OR¹⁰, —SR¹⁰, —CN, —F, —Cl, —Br, —I, —NR¹⁰R^(10′),    (C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl; hydroxy-(C₁-C₆)-alkyl, —C(O)—H,    —C(O)—(C₁-C₆)-alkyl, —C(O)—OH, or —C(O)—O—(C₁-C₆)-alkyl;-   R¹⁰ and R^(10′) are independently selected from the group consisting    of H, (C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl, aryl, aryl-(C₁-C₆)-alkyl,    heteroaryl, heterocyclyl, —C(O)—H, —C(O)—(C₁-C₆)-alkyl, —C(O)-aryl,    and —C(O)—(C₁-C₆)-alkyl-aryl; or-   R¹⁰ and R^(10′) together with the atom to which they are attached    form a saturated or unsaturated 3-8 membered ring, optionally    incorporating one or more additional heteroatoms independently    selected from one, two, or three N, O, or S atoms, and optionally    substituted with one or more substituents independently selected    from oxo, —OH, —F, —Cl, —Br, —I, —NR¹¹R^(11′), (C₁-C₆)-alkyl,    (C₁-C₆)-alkoxy; (C₁-C₆)-haloalkyl; hydroxy-(C₁-C₆)-alkyl, —C(O)—H,    —C(O)—(C₁-C₆)-alkyl, —C(O)OH, and —C(O)O—(C₁-C₆)-alkyl;-   R¹¹ and R^(11′) are independently selected from hydrogen and    (C₁-C₆)-alkyl; or-   R¹¹ and R^(11′) together with the atom to which they are attached    form a saturated or unsaturated 3-8 membered ring, optionally    incorporating one or more additional heteroatoms independently    selected from one, two, or three N, O, or S atoms, and optionally    substituted with oxo, —OR¹⁰, —SR¹⁰, —CN, —F, —Cl, —Br, —I, NH₂,    —NH(C₁-C₄)-alkyl, —N((C₁-C₄)-alkyl)₂, (C₁-C₆)-alkyl,    (C₁-C₆)-haloalkyl; hydroxy-(C₁-C₆)-alkyl, —C(O)—H,    —C(O)—(C₁-C₆)-alkyl, —C(O)—OH, or —C(O)—O—(C₁-C₆)-alkyl; and    with the proviso that the compounds are not:    -   N-(4-(1H-imidazol-1-yl)phenyl)-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)propanamide;        N-(2-(4-decylpiperazin-1-yl)-1-phenylethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;        N-(2-(4-(10-hydroxydecyl)piperazin-1-yl)-1-phenylethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;        N-(2-(4-(10-hydroxydecyl)piperazin-1-yl)-2-oxo-1-phenylethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;        or        N-(4-hydroxy-3,5-dimethylphenyl)-5-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)pentanamide;        and all salts, stereoisomers, mixtures of stereoisomers,        prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIa,where R¹, R², and R³ are independently of each other selected frommethyl, ethyl, propyl i-propyl, butyl, sec-butyl or i-butyl; and allsalts, stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof. In some embodiments, R¹, R², and R³ aremethyl.

In another embodiment, the invention embraces compounds of formula IIIa,where A is a branched alkylene, and all salts, stereoisomers, mixturesof stereoisomers, prodrugs, metabolites, solvates, and hydrates thereof.In some embodiments, A is —CH₂—CH₂—C(CH₃)₂—. In other embodiments A is—CH₂—CH₂—CH(CH₃)—. In other embodiments A is —(CH₂)₂-cyclopropyl- or—(CH₂)₂-cyclobutyl-.

In another embodiment, the invention embraces compounds of formula IIIa,where R³⁰ is independently selected from hydrogen, and (C₁-C₆)-alkyloptionally substituted with hydroxy, alkoxy or —C(O)O—(C₁-C₆)-alkyl, andall salts, stereoisomers, mixtures of stereoisomers, prodrugs,metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIa,where R⁴ is hydrogen and R³⁰ is unsubstituted (C₁-C₆)-alkyl; and inanother embodiment R³⁰ is selected from methyl, ethyl, propyl,isopropyl, butyl, isobutyl, 2-methylbutyl, and cyclopropyl; and allsalts, stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIa,where R⁴ is hydrogen and R³⁰ is (C₁-C₆)-alkyl substituted with hydroxy,alkoxy or —C(O)O—(C₁-C₆)-alkyl; and all salts, stereoisomers, mixturesof stereoisomers, prodrugs, metabolites, solvates, and hydrates thereof.In another embodiment, the invention embraces compounds of formula IIIa,where R⁴ is hydrogen and R³⁰ is (C₁-C₆)-alkyl substituted with hydroxy,and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,metabolites, solvates, and hydrates thereof. In another embodiment, theinvention embraces compounds of formula IIIa, where R⁴ is hydrogen andR³⁰ is selected from —(CH₂)₁₋₆—OH; 1-hydroxyprop-2-yl and2-hydroxyprop-1-yl; and all salts, stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIa,where R⁴ is methyl and R³⁰ are independently selected from (C₁-C₆)-alkylsubstituted with hydroxyl; for example R³⁰ is —CH₂—CH₂—OH; and allsalts, stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIa,where R⁴ is hydrogen and R³⁰ is independently selected from(C₁-C₆)-alkyl substituted with —NR¹⁰R^(10′), where R¹⁰ and R^(10′) areindependently selected from the group consisting of hydrogen,(C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl, aryl, aryl-(C₁-C₆)-alkyl, heteroaryl,heterocyclyl, —C(O)—H, —C(O)—(C₁-C₆)-alkyl, —C(O)-aryl and—C(O)—(C₁-C₆)-alkyl-aryl; and all salts, stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof. Inanother embodiment, the invention embraces compounds of formula IIIa,where R⁴ is hydrogen and R³⁰ is independently selected from(C₁-C₆)-alkyl substituted with —NH₂, —NH(C₁-C₆)-alkyl, or—N((C₁-C₆)-alkyl)₂, for example where R³ is dimethylaminoethyl; and allsalts, stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof. In another embodiment, the inventionembraces pharmaceutically acceptable salts of compounds of formula IIIa,where R⁴ is hydrogen and R³⁰ is dimethylaminoethyl; for examplehydrochloride or mesylate salts.

In another embodiment, the invention embraces compounds of formula IIIa,where R⁴ is hydrogen and R⁶ is (C₁-C₆)-alkyl optionally substituted withphenyl, for example benzyl or phenylethyl, and all salts, stereoisomers,mixtures of stereoisomers, prodrugs, metabolites, solvates, and hydratesthereof.

In another embodiment, the invention embraces compounds of formula IIIa,where R⁴ is hydrogen and R³⁰ is (C₁-C₆)-alkyl optionally substitutedwith heterocyclyl or heteroaryl; and all salts, stereoisomers, mixturesof stereoisomers, prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIa,where R⁴ is hydrogen and R³⁰ is (C₁-C₆)-alkyl optionally substitutedwith a nitrogen containing heterocyclyl and all salts, stereoisomers,mixtures of stereoisomers, prodrugs, metabolites, solvates, and hydratesthereof. In another embodiment the invention embraces compounds offormula IIIa, where R⁴ is hydrogen and R³⁰ is (C₁-C₆)-alkyl optionallysubstituted with pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl,and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIa,where R⁴ is hydrogen and R³⁰ is (C₁-C₆)-alkyl optionally substitutedwith a nitrogen containing heteroaryl, for example imidazolyl,pyridinyl, pyrrolyl, and pyrimidinyl, and all salts, stereoisomers,mixtures of stereoisomers, prodrugs, metabolites, solvates, and hydratesthereof. In another embodiment, the invention embraces compounds offormula IIIa, where R⁴ is hydrogen and R³⁰ is (C₁-C₆)-alkyl optionallysubstituted with a nitrogen containing heteroaryl, for exampleimidazol-1-yl or pyridin-2-yl and all salts, stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof. Inanother embodiment, the invention embraces compounds of formula IIIa,where R⁴ is hydrogen and R³⁰ is 3-(1H-imidazol-1-yl)propyl,pyridin-2-ylmethyl, or 2-(pyridin-2-yl)ethyl, and all salts,stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIa,where R⁴ is hydrogen and R³⁰ is (C₁-C₆)-alkyl optionally substitutedwith an oxygen or sulfur containing heterocyclyl or heteroaryl, forexample tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl,pyranyl, furanyl, thienyl, benzopyranyl, or benzofuranyl; and all salts,stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIa,where R⁴ is hydrogen and R³⁰ is optionally substituted aryl, for examplephenyl optionally substituted with one or more substituentsindependently selected from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl,and (C₁-C₆)-alkoxy; and all salts, stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIa,where R⁴ is hydrogen and R³⁰ is benzo[d][1,3]dioxole or2,3-dihydrobenzo[b][1,4]-dioxine; and all salts, stereoisomers, mixturesof stereoisomers, prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIa,where R⁴ and R³⁰ together with the nitrogen atom to which they areattached form an optionally substituted 3 to 8-membered nitrogencontaining heterocyclyl ring, for example an azetidine, a pyrrolidine, apiperidine, a piperazine, a morpholine or an azepane ring; and allsalts, stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIa,where R⁴ and R³⁰ together with the nitrogen atom to which they areattached form piperidin-1-yl, 4-hydroxy-piperidin-1-yl,4-methyl-piperazin-1-yl, 4-benzyl-piperazin-1-yl, and azepan-1-yl andall salts, stereoisomers, mixtures of stereoisomers, prodrugs,metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIb:

where:

-   A is (C₁-C₄)-alkylene, (C₂-C₄)-alkenylene, or (C₂-C₄)-alkynylene;-   B is —C(O)NR⁴— or —S(O)₂NR⁴—;-   R¹, R², and R³ are independently unsubstituted (C₁-C₆)-alkyl;-   R⁴ is hydrogen or (C₁-C₆)-alkyl;-   R³⁰ is hydrogen, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,    aryl, or heterocyclyl,    -   where the alkyl, alkenyl or alkynyl groups may optionally be        substituted with —OR¹⁰, —SR¹⁰, —CN, —F, —Cl, —Br, —I,        —NR¹⁰R^(10′), oxo, (C₃-C₆)-cycloalkyl, aryl, aryl-(C₁-C₆)-alkyl,        heteroaryl, heterocyclyl, —C(O)—R¹¹, —C(O)—C₀-C₆-alkyl-aryl,        —C(O)—O—R¹¹, —C(O)—O—(C₀-C₆)-alkyl-aryl, —C(O)—N—R¹¹R^(11′),        —C(O)—N—(C₀-C₆)-alkyl-aryl, —N—C(O)—R¹¹,        —N—C(O)—(C₀-C₆)-alkyl-aryl; or where one of the carbons of the        alkyl, alkenyl, or alkynyl groups may be replaced by a        heteroatom selected from O, N or S; and    -   where the aryl, heteroaryl and heterocyclyl rings may be further        substituted with (C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl, —CN, —F, —Cl,        —Br, —I, —NR¹⁰R^(10′), oxo, hydroxy, (C₁-C₆)-alkoxy,        —C(O)—(C₁-C₆)-alkyl and —C(O)—O—(C₁-C₆)-alkyl; or-   R³⁰ and R⁴ together with the atom to which they are attached form a    saturated or unsaturated 3-8 membered ring, optionally incorporating    one or more additional heteroatoms independently selected from one,    two, or three, N, O, or S atoms, and optionally substituted with    oxo, —OR¹⁰, —SR¹⁰, —CN, —F, —Cl, —Br, —I, —NR¹⁰R^(10′),    (C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl; hydroxy-(C₁-C₆)-alkyl, —C(O)—H,    —C(O)—(C₁-C₆)-alkyl, —C(O)—OH, or —C(O)—O—(C₁-C₆)-alkyl;-   R¹⁰ and R^(10′) are independently selected from the group consisting    of H, (C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl, aryl, aryl-(C₁-C₆)-alkyl,    heteroaryl, heterocyclyl, —C(O)—H, —C(O)—(C₁-C₆)-alkyl, —C(O)-aryl,    and —C(O)—(C₁-C₆)-alkyl-aryl; or-   R¹⁰ and R^(10′) together with the atom to which they are attached    form a saturated or unsaturated 3-8 membered ring, optionally    incorporating one or more additional heteroatoms independently    selected from one, two, or three, N, O, or S atoms, and optionally    substituted with one or more substituents independently selected    from oxo, —OH, —F, —Cl, —Br, —I, —NR¹¹R^(11′), (C₁-C₆)-alkyl,    (C₁-C₆)-alkoxy; (C₁-C₆)-haloalkyl; hydroxy-(C₁-C₆)-alkyl, —C(O)—H,    —C(O)—(C₁-C₆)-alkyl, —C(O)OH, and —C(O)O—(C₁-C₆)-alkyl;-   R¹¹ and R^(11′) are independently selected from hydrogen and    (C₁-C₆)-alkyl; or-   R¹¹ and R^(11′) together with the atom to which they are attached    form a saturated or unsaturated 3-8 membered ring, optionally    incorporating one or more additional, such as one, two, or three, N,    O, or S atoms and optionally substituted with oxo, —OR¹⁰, —SR¹⁰,    —CN, —F, —Cl, —Br, —I, NH₂, —NH(C₁-C₄)-alkyl, —N((C₁-C₄)-alkyl)₂,    (C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl; hydroxy-(C₁-C₆)-alkyl, —C(O)—H,    —C(O)—(C₁-C₆)-alkyl, —C(O)—OH, or —C(O)—O—(C₁-C₆)-alkyl; and-   M and M′ are independently selected from hydrogen, —C(O)—R¹²,    —C(O)—(C₂-C₆)-alkenyl, —C(O)—(C₂-C₆)-alkynyl, —C(O)-aryl;    —C(O)-heteroaryl, —C(O)O—R¹², —C(O)NR¹²R¹², —SO₂OR¹²,    —SO₂—(C₁-C₆)-alkyl, —SO₂—(C₁-C₆)-haloalkyl; —SO₂-aryl, —SO₂—NR¹²R¹²,    —P(O)(OR¹²)(OR¹²), and C-linked mono- or di-peptide, where R¹² is    hydrogen or (C₁-C₆)-alkyl optionally substituted with —OH, —NH₂,    NH((C₁-C₄)-alkyl), —N((C₁-C₄)-alkyl)₂, —C(O)—OH,    —C(O)—O—(C₁-C₄)-alkyl or halogen;    with the proviso that the compound is not;-   5-(2,5-dihydroxy-3,4,6-trimethylphenyl)-N-(4-hydroxy-3,5-dimethylphenyl)pentanamide;    and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIb,where R¹, R², and R³ are independently of each other selected frommethyl, ethyl, propyl i-propyl, butyl, sec-butyl or i-butyl; and M andM′ are hydrogen; and all salts, stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof. Insome embodiments, R¹, R², and R³ are methyl and M and M′ are hydrogen.

In another embodiment, the invention embraces compounds of formula IIIb,where A is a branched alkylene, and M and M′ are hydrogen; and all saltsstereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof. In some embodiments, A is—CH₂—CH₂—C(CH3)₂— and M and M′ are hydrogen. In other embodiments A is—CH₂—CH₂—CH(CH₃)— and M and M′ are hydrogen. In other embodiments A is—(CH₂)₂-cyclopropyl- or —(CH₂)₂-cyclobutyl- and M and M′ are hydrogen.

In another embodiment, the invention embraces compounds of formula IIIb,where R³⁰ is independently selected from hydrogen, and (C₁-C₆)-alkyloptionally substituted with hydroxy, alkoxy or —C(O)O—(C₁-C₆)-alkyl, andM and M′ are hydrogen; and all salts stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIb,where R⁴ is hydrogen and R³⁰ is unsubstituted (C₁-C₆)-alkyl, and M andM′ are hydrogen; and in another embodiment R³⁰ is selected from methyl,ethyl, propyl, isopropyl, butyl, isobutyl, 2-methylbutyl, andcyclopropyl and M and M′ are hydrogen; and all salts stereoisomers,mixtures of stereoisomers, prodrugs, metabolites, solvates, and hydratesthereof.

In another embodiment, the invention embraces compounds of formula IIIb,where R⁴ is hydrogen and R³⁰ is (C₁-C₆)-alkyl substituted with hydroxy,alkoxy or —C(O)O—(C₁-C₆)-alkyl, and M and M′ are hydrogen; and allsalts, stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof. In another embodiment, the inventionembraces compounds of formula IIIb, where R⁴ is hydrogen, R³⁰ is(C₁-C₆)-alkyl substituted with hydroxy, and M and M′ are hydrogen; andall salts, stereoisomers, mixtures of stereoisomers, prodrugs,metabolites, solvates, and hydrates thereof. In another embodiment, theinvention embraces compounds of formula IIIb, where R⁴ is hydrogen; R³⁰is selected from —(CH₂)₁₋₆—OH; 1-hydroxyprop-2-yl and2-hydroxyprop-1-yl; and M and M′ are hydrogen; and all salts,stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIb,where R⁴ is methyl; R³⁰ are independently selected from (C₁-C₆)-alkylsubstituted with hydroxyl; and M and M′ are hydrogen; for example R³⁰ is—CH₂—CH₂—OH; and M and M′ are hydrogen; and all salts, stereoisomers,mixtures of stereoisomers, prodrugs, metabolites, solvates, and hydratesthereof.

In another embodiment, the invention embraces compounds of formula IIIb,where R⁴ is hydrogen; R³⁰ is independently selected from (C₁-C₆)-alkylsubstituted with —NR¹⁰R^(10′), where R¹⁰ and R^(10′) are independentlyselected from the group consisting of hydrogen, (C₁-C₆)-alkyl,(C₁-C₆)-haloalkyl, aryl, aryl-(C₁-C₆)-alkyl, heteroaryl, heterocyclyl,—C(O)—H, —C(O)—(C₁-C₆)-alkyl, —C(O)-aryl and —C(O)—(C₁-C₆)-alkyl-aryl,and M and M′ are hydrogen; and all salts, stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof. Inanother embodiment, the invention embraces compounds of formula IIIb,where R⁴ is hydrogen; R³⁰ is independently selected from (C₁-C₆)alkylsubstituted with —NH₂, —NH((C₁-C₆)-alkyl), or —N((C₁-C₆)-alkyl)₂, and Mand M′ are hydrogen, for example where R³⁰ is dimethylaminoethyl; andall salts, stereoisomers, mixtures of stereoisomers, prodrugs,metabolites, solvates, and hydrates thereof. In another embodiment, theinvention embraces pharmaceutically acceptable salts of compounds offormula IIIb, where R⁴ is hydrogen; R³⁰ is dimethylaminoethyl and M andM′ are hydrogen; for example hydrochloride or mesylate salts.

In another embodiment, the invention embraces compounds of formula IIIb,where R⁴ is hydrogen; R⁶ is (C₁-C₆)alkyl optionally substituted withphenyl, and M and M′ are hydrogen, for example benzyl or phenethyl, andall salts, stereoisomers, mixtures of stereoisomers, prodrugs,metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIb,where R⁴ is hydrogen; R³⁰ is (C₁-C₆)-alkyl optionally substituted withheterocyclyl or heteroaryl, and M and M′ are hydrogen; and all salts,stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIb,where R⁴ is hydrogen; R³⁰ is (C₁-C₆)-alkyl optionally substituted with anitrogen containing heterocyclyl, and M and M′ are hydrogen; and allsalts, stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof. In another embodiment, the inventionembraces compounds of formula IIIb, where R⁴ is hydrogen; Ra³⁰ is(C₁-C₆)-alkyl optionally substituted with pyrrolidinyl, piperidinyl,piperazinyl, or morpholinyl, and M and M′ are hydrogen; and all salts,stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIb,where R⁴ is hydrogen; R³⁰ is (C₁-C₆)-alkyl optionally substituted with anitrogen containing heteroaryl, for example imidazolyl, pyridinyl,pyrrolyl, and pyrimidinyl, and M and M′ are hydrogen; and all salts,stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof. In another embodiment, the inventionembraces compounds of formula IIIb, where R⁴ is hydrogen; R³⁰ is(C₁-C₆)-alkyl optionally substituted with a nitrogen containingheteroaryl, for example imidazol-1-yl or pyridin-2-yl, and M and M′ arehydrogen; and all salts, stereoisomers, mixtures of stereoisomers,prodrugs, metabolites, solvates, and hydrates thereof. In anotherembodiment, the invention embraces compounds of formula IIIb, where R⁴is hydrogen; R³⁰ is 3-(1H-imidazol-1-yl)propyl, pyridin-2-ylmethyl, or2-(pyridin-2-yl)ethyl, and M and M′ are hydrogen; and all salts,stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIb,where R⁴ is hydrogen; R³⁰ is (C₁-C₆)-alkyl optionally substituted withan oxygen or sulfur containing heterocyclyl or heteroaryl, for exampletetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyranyl,furanyl, thienyl, benzopyranyl, or benzofuranyl, and M and M′ arehydrogen; and all salts, stereoisomers, mixtures of stereoisomers,prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIb,where R⁴ is hydrogen; R³⁰ is optionally substituted aryl, for examplephenyl optionally substituted with one or more substituentsindependently selected from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-haloalkyl,and (C₁-C₆)-alkoxy, and M and M′ are hydrogen; and all salts,stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIb,where R⁴ is hydrogen; R³⁰ is benzo[d][1,3]dioxole or2,3-dihydrobenzo[b][1,4]dioxine, and M and M′ are hydrogen; and allsalts, stereoisomers, mixtures of stereoisomers, prodrugs, metabolites,solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIb,where R⁴ and R³⁰ together with the nitrogen atom to which they areattached form an optionally substituted 3 to 8-membered nitrogencontaining heterocyclyl ring, for example an azetidine, a pyrrolidine, apiperidine, a piperazine, a morpholine or an azepane ring, and M and M′are hydrogen; and all salts, stereoisomers, mixtures of stereoisomers,prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula IIIb,where R⁴ and R³⁰ together with the nitrogen atom to which they areattached form piperidin-1-yl, 4-hydroxy-piperidin-1-yl,4-methyl-piperazin-1-yl, 4-benzyl-piperazin-1-yl, and azepan-1-yl, and Mand M′ are hydrogen; and all salts, stereoisomers, mixtures ofstereoisomers, prodrugs, metabolites, solvates, and hydrates thereof.

In another embodiment, the invention embraces compounds of formula I,selected from:

-   N-propyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-hydroxyethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2,3,5-trimethyl-6-(4-(4-methylpiperazin-1-yl)-4-oxobutyl)cyclohexa-2,5-diene-1,4-dione;-   2-(4-(4-hydroxypiperidin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(4-benzylpiperazin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(4-acetylpiperazin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;    -   2-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(4-benzoylpiperazin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(4-(cyclohexanecarbonyl)piperazin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   N-phenethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-(4-(4-fluoropiperidin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(4,4-difluoropiperidin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   N-(4-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-methoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-p-tolyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,4-dimethoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-(trifluoromethyl)phenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(benzo[d][1,3]dioxol-5-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-methoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-methoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2,2-dimethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,3-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,5-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,4-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,5-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;N-(pyridin-3-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(pyridin-4-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-hydroxyethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-methyl-N-phenethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorophenyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,6-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(pyridin-2-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-cyanophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,5-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,6-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,4-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,5-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-methyl-N-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-chlorophenyl)-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorophenyl)-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-cyanophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(pyridin-3-ylmethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-(pyridin-2-yl)ethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-(pyridin-4-yl)ethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-aminophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-(4-(4-acetylpiperazin-1-yl)-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(4-fluoropiperidin-1-yl)-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-methyl-N-propyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-amino-4-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-methyl-N-(pyridin-2-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-chlorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-chlorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-chlorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-fluorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-fluorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-chlorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-chlorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-chlorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N,N-dimethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-(4-(azetidin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   N-(2-hydroxyethyl)-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-(4-(indolin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(isoindolin-2-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(3-hydroxyazetidin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(3,4-dihydroquinolin-1    (2H)-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   N-(3-cyanophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-N-ethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-N-isopropyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-hydroxy-2-methylpropyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-((1-hydroxycyclopropyl)methyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2,3,5-trimethyl-6-(4-morpholino-4-oxobutyl)cyclohexa-2,5-diene-1,4-dione;-   2,3,5-trimethyl-6-(4-oxo-4-(pyrrolidin-1-yl)butyl)cyclohexa-2,5-diene-1,4-dione;-   N-(1-hydroxy-2-methylpropan-2-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-(4-(4-hydroxypiperidin-1-yl)-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   N-(3-(1H-imidazol-1-yl)propyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2,3,5-trimethyl-6-(4-morpholino-4-oxobutyl)cyclohexa-2,5-diene-1,4-dione;-   2,3,5-trimethyl-6-(3-methyl-4-morpholino-4-oxobutyl)cyclohexa-2,5-diene-1,4-dione;-   2,3,5-trimethyl-6-(4-oxo-4-(piperidin-1-yl)butyl)cyclohexa-2,5-diene-1,4-dione;-   N-(2-hydroxyethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2,3,5-trimethyl-6-(2-methyl-4-oxo-4-(piperidin-1-yl)butyl)cyclohexa-2,5-diene-1,4-dione;-   N-ethyl-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)propanamide;-   N-ethyl-2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienecarboxamide;-   2,3,5-trimethyl-6-(2-(1-(4-methylpiperazine-1-carbonyl)cyclobutyl)ethyl)cyclohexa-2,5-diene-1,4-dione;-   N,N-dimethyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-cyclobutanecarboxamide;-   1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)cyclobutanecarboxamide;-   2,2-dimethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2,2-dimethyl-N-propyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-hydroxyethyl)-2,2-dimethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-(4-(4-acetylpiperazin-1-yl)-3,3-dimethyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   4-(5-methoxy-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   4-(2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   4-(4-methoxy-2,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    and-   4-(2-methoxy-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    and all salts, stereoisomers, mixtures of stereoisomers, prodrugs,    metabolites, solvates, and hydrates thereof.

In one embodiment, including any of the foregoing embodiments, theinvention embraces a method of treating or suppressing an oxidativestress disorder selected from a mitochondrial disorder, an impairedenergy processing disorder, a neurodegenerative disorder and a diseaseof aging, modulating one or more energy biomarkers, normalizing one ormore energy biomarkers, or enhancing one or more energy biomarkers, byadministering a therapeutically effective amount of one or morecompounds of Formulae Q, QH, I, Ia, Ib, II, IIa, IIb, III, IIIa or IIIb.

In other embodiments, including any of the foregoing embodiments, theoxidative stress disorder is a mitochondrial disorder selected from thegroup consisting of mitochondrial diseases; Myoclonic Epilepsy withRagged Red Fibers (MERRF); Mitochondrial Myopathy, Encephalopathy,Lactacidosis, and Stroke (MELAS); Maternally Inherited Diabetes andDeafness (MIDD), Leber's Hereditary Optic Neuropathy (LHON); chronicprogressive external ophthalmoplegia (CPEO); Leigh Disease; Kearns-SayreSyndrome (KSS); Friedreich's Ataxia (FRDA); Co-Enzyme Q10 (CoQ10)Deficiency; Complex I Deficiency; Complex II Deficiency; Complex IIIDeficiency; Complex IV Deficiency; Complex V Deficiency; othermyopathies; cardiomyopathy; encephalomyopathy; renal tubular acidosis;neurodegenerative diseases; Parkinson's disease; Alzheimer's disease;amyotrophic lateral sclerosis (ALS); motor neuron diseases; hearing andbalance impairments; or other neurological disorders; epilepsy; geneticdiseases; Huntington's Disease; mood disorders; schizophrenia; bipolardisorder; age-associated diseases; cerebral vascular diseases; maculardegeneration; diabetes; and cancer.

In another embodiment, including any of the foregoing embodiments, themitochondrial disorder is a mitochondrial respiratory chain disorder. Ina particular embodiment, the mitochondrial respiratory chain disorder isa respiratory protein chain disorder. In another particular embodiment,the disorder is CoQ10 deficiency.

In another embodiment, including any of the foregoing embodiments, themitochondrial disorder is selected from the group consisting ofinherited mitochondrial diseases; Myoclonic Epilepsy with Ragged RedFibers (MERRF); Mitochondrial Myopathy, Encephalopathy, Lactacidosis,and Stroke (MELAS); Maternally Inherited Diabetes and Deafness (MIDD),Leber's Hereditary Optic Neuropathy (LHON); chronic progressive externalophthalmoplegia (CPEO); Leigh Disease; Kearns-Sayre Syndrome (KSS); andFriedreich's Ataxia (FRDA).

In another embodiment of the invention, including any of the foregoingembodiments, the mitochondrial disorder is Friedreich's ataxia (FRDA).In another embodiment of the invention, the mitochondrial disorder isLeber's Hereditary Optic Neuropathy (LHON). In another embodiment of theinvention, including any of the foregoing embodiments, the mitochondrialdisorder is mitochondrial myopathy, encephalopathy, lactacidosis, andstroke (MELAS). In another embodiment of the invention including any ofthe foregoing embodiments the mitochondrial disorder is MaternallyInherited Diabetes and Deafness (MIDD). In another embodiment of theinvention, including any of the foregoing embodiments, the mitochondrialdisorder is Kearns-Sayre Syndrome (KSS). In another embodiment of theinvention, the mitochondrial disorder is Myoclonic Epilepsy with RaggedRed Fibers (MERRF). In another embodiment of the invention, themitochondrial disorder is Maternally Inherited Diabetes and Deafness(MIDD). In another embodiment of the invention, the mitochondrialdisorder is Co-Enzyme Q10 (CoQ10) deficiency. In another embodiment ofthe invention, including any of the foregoing embodiments, the disorderis Parkinson's disease. In another embodiment of the invention,including any of the foregoing embodiments, the disorder is Huntington'sdisease. In another embodiment of the invention, including any of theforegoing embodiments, the disorder is amyotrophic lateral sclerosisdisease (ALS). In another embodiment, the disorder is cerebral vascularaccidents. In another embodiment, the disorder is hearing or balanceimpairment.

In another embodiment of the invention, including any of the foregoingembodiments, the compounds described herein are administered to subjectsaffected with a pervasive development disorder such as AutisticDisorder, Asperger's Disorder, Childhood Disintegrative Disorder (CDD),Rett's Disorder, and PDD-Not Otherwise Specified (PDD-NOS).

In another embodiment of the invention, including any of the foregoingembodiments, the compounds described herein are administered to subjectsaffected with an impaired energy processing disorder due to deprivation,poisoning or toxicity of oxygen, or of qualitative or quantitativedisruption in the transport of oxygen.

In another embodiment of the invention, including any of the foregoingembodiments, the compounds described herein are administered to subjectsaffected with diseases where qualitative and/or quantitative disruptionsin the transport of oxygen to tissues result in energy disruption in thefunction of red cells. In some embodiments, the diseases include oxygenpoisoning and haemoglobinopathies, such as sickle-cell disease andthalassemia.

In another embodiment of the invention, including any of the foregoingembodiments, the compounds described herein are administered to subjectssuffering from a mitochondrial disorder to modulate one or more ofvarious energy biomarkers, including, but not limited to, lactic acid(lactate) levels, either in whole blood, plasma, cerebrospinal fluid, orcerebral ventricular fluid; pyruvic acid (pyruvate) levels, either inwhole blood, plasma, cerebrospinal fluid, or cerebral ventricular fluid;lactate/pyruvate ratios, either in whole blood, plasma, cerebrospinalfluid, or cerebral ventricular fluid; phosphocreatine levels, NADH(NADH+H⁺) or NADPH (NADPH+H⁺) levels; NAD or NADP levels; ATP levels;reduced coenzyme Q (CoQ^(red)) levels; oxidized coenzyme Q (CoQ^(ox))levels; total coenzyme Q (CoQ^(tot)) levels; oxidized cytochrome Clevels; reduced cytochrome C levels; oxidized cytochrome C/reducedcytochrome C ratio; acetoacetate levels; beta-hydroxy butyrate levels;acetoacetate/beta-hydroxy butyrate ratio; 8-hydroxy-2′-deoxyguanosine(8-OHdG) levels; levels of reactive oxygen species; oxygen consumption(VO2), carbon dioxide output (VCO2), respiratory quotient (VCO2/VO2),and to modulate exercise intolerance (or conversely, modulate exercisetolerance) and to modulate anaerobic threshold. Energy biomarkers can bemeasured in whole blood, plasma, cerebrospinal fluid, cerebroventricularfluid, arterial blood, venous blood, or any other body fluid, body gas,or other biological sample useful for such measurement. In oneembodiment, the levels are modulated to a value within about 2 standarddeviations of the value in a healthy subject. In another embodiment, thelevels are modulated to a value within about 1 standard deviation of thevalue in a healthy subject. In another embodiment, the levels in asubject are changed by at least about 10% above or below the level inthe subject prior to modulation. In another embodiment, the levels arechanged by at least about 20% above or below the level in the subjectprior to modulation. In another embodiment, the levels are changed by atleast about 30% above or below the level in the subject prior tomodulation. In another embodiment, the levels are changed by at leastabout 40% above or below the level in the subject prior to modulation.In another embodiment, the levels are changed by at least about 50%above or below the level in the subject prior to modulation. In anotherembodiment, the levels are changed by at least about 75% above or belowthe level in the subject prior to modulation. In another embodiment, thelevels are changed by at least about 100% above or at least about 90%below the level in the subject prior to modulation.

In another embodiment, including any of the foregoing embodiments, thesubject or subjects in which a method of treating or suppressing anoxidative stress disorder, modulating one or more energy biomarkers,normalizing one or more energy biomarkers, or enhancing one or moreenergy biomarkers is performed is/are selected from the group consistingof subjects undergoing strenuous or prolonged physical activity;subjects with chronic energy problems; subjects with chronic respiratoryproblems; pregnant females; pregnant females in labor; neonates;premature neonates; subjects exposed to extreme environments; subjectsexposed to hot environments; subjects exposed to cold environments;subjects exposed to environments with lower-than-average oxygen content;subjects exposed to environments with higher-than-average carbon dioxidecontent; subjects exposed to environments with higher-than-averagelevels of air pollution; airline travelers; flight attendants; subjectsat elevated altitudes; subjects living in cities with lower-than-averageair quality; subjects working in enclosed environments where air qualityis degraded; subjects with lung diseases; subjects withlower-than-average lung capacity; tubercular patients; lung cancerpatients; emphysema patients; cystic fibrosis patients; subjectsrecovering from surgery; subjects recovering from illness; elderlysubjects; elderly subjects experiencing decreased energy; subjectssuffering from chronic fatigue; subjects suffering from chronic fatiguesyndrome; subjects undergoing acute trauma; subjects in shock; subjectsrequiring acute oxygen administration; subjects requiring chronic oxygenadministration; or other subjects with acute, chronic, or ongoing energydemands who can benefit from enhancement of energy biomarkers.

In another embodiment, the invention embraces one or more compounds ofFormula Q, Formula QH, Formula I, Formula Ia, Formula Ib, Formula II,Formula IIa, Formula IIb, Formula IIIa and/or Formula IIIb incombination with a pharmaceutically acceptable excipient, carrier, orvehicle.

In another embodiment, the invention embraces the use of one or morecompounds of Formula Q, Formula QH, Formula I, Formula Ia, Formula Ib,Formula II, Formula IIa, Formula IIb, Formula III, Formula IIIa and/orFormula IIIb, in the therapy of mitochondrial disease. In anotherembodiment, the invention embraces the use of one or more compounds ofFormula Q, Formula QH, Formula I, Formula Ia, Formula Ib, Formula II,Formula IIa, Formula IIb, Formula III, Formula IIIa and/or Formula IIIb,in the manufacture of a medicament for use in therapy of mitochondrialdisease.

For all of the compounds and methods described above, the quinone formcan also be used in its reduced (hydroquinone) form when desired.Likewise, the hydroquinone form can also be used in its oxidized(quinone) form when desired.

Modes For Carrying Out The Invention

The invention embraces compounds useful in treating or suppressingdiseases, developmental delays and symptoms related to oxidative stresssuch as mitochondrial disorders, impaired energy processing disorders,neurodegenerative diseases and diseases of aging, and methods of usingsuch compounds for modulation of energy biomarkers. The redox activetherapeutics for treatment or suppression of said diseases andassociated aspects of the invention are described in more detail herein.

By “subject,” “individual,” or “patient” is meant an individualorganism, preferably a vertebrate, more preferably a mammal, mostpreferably a human.

“Treating” a disease with the compounds and methods discussed herein isdefined as administering one or more of the compounds discussed herein,with or without additional therapeutic agents, in order to reduce oreliminate either the disease or one or more symptoms of the disease, orto retard the progression of the disease or of one or more symptoms ofthe disease, or to reduce the severity of the disease or of one or moresymptoms of the disease. “Suppression” of a disease with the compoundsand methods discussed herein is defined as administering one or more ofthe compounds discussed herein, with or without additional therapeuticagents, in order to suppress the clinical manifestation of the disease,or to suppress the manifestation of adverse symptoms of the disease. Thedistinction between treatment and suppression is that treatment occursafter adverse symptoms of the disease are manifest in a subject, whilesuppression occurs before adverse symptoms of the disease are manifestin a subject. Suppression may be partial, substantially total, or total.Because many of the mitochondrial disorders are inherited, geneticscreening can be used to identify patients at risk of the disease. Thecompounds and methods of the invention can then be administered toasymptomatic patients at risk of developing the clinical symptoms of thedisease, in order to suppress the appearance of any adverse symptoms.“Therapeutic use” of the compounds discussed herein is defined as usingone or more of the compounds discussed herein to treat or suppress adisease, as defined above. An “effective amount” of a compound is anamount of the compound sufficient to modulate, normalize, or enhance oneor more energy biomarkers (where modulation, normalization, andenhancement are defined below). A “therapeutically effective amount” ofa compound is an amount of the compound, which, when administered to asubject, is sufficient to reduce or eliminate either a disease or one ormore symptoms of a disease, or to retard the progression of a disease orof one or more symptoms of a disease, or to reduce the severity of adisease or of one or more symptoms of a disease, or to suppress theclinical manifestation of a disease, or to suppress the manifestation ofadverse symptoms of a disease. A therapeutically effective amount can begiven in one or more administrations. An “effective amount” of acompound embraces both a therapeutically effective amount, as well as anamount effective to modulate, normalize, or enhance one or more energybiomarkers in a subject.

By “respiratory chain disorder” is meant a disorder which results in thedecreased utilization of oxygen by a mitochondrion, cell, tissue, orindividual, due to a defect or disorder in a protein contained in themitochondrial respiratory chain. By “respiratory chain” is meant thecomponents (including, but not limited to, proteins, tetrapyrroles, andcytochromes) comprising mitochondrial complex I, II, III, IV, and/or V;“respiratory chain protein” refers to the protein components of thosecomplexes.

“Modulation” of, or to “modulate,” an energy biomarker means to changethe level of the energy biomarker towards a desired value, or to changethe level of the energy biomarker in a desired direction (e.g., increaseor decrease). Modulation can include, but is not limited to,normalization and enhancement as defined below.

“Normalization” of, or to “normalize,” an energy biomarker is defined aschanging the level of the energy biomarker from a pathological valuetowards a normal value, where the normal value of the energy biomarkercan be 1) the level of the energy biomarker in a healthy person orsubject, or 2) a level of the energy biomarker that alleviates one ormore undesirable symptoms in the person or subject. That is, tonormalize an energy biomarker which is depressed in a disease statemeans to increase the level of the energy biomarker towards the normal(healthy) value or towards a value which alleviates an undesirablesymptom; to normalize an energy biomarker which is elevated in a diseasestate means to decrease the level of the energy biomarker towards thenormal (healthy) value or towards a value which alleviates anundesirable symptom.

“Enhancement” of, or to “enhance,” energy biomarkers means tointentionally change the level of one or more energy biomarkers awayfrom either the normal value, or the value before enhancement, in orderto achieve a beneficial or desired effect. For example, in a situationwhere significant energy demands are placed on a subject, it may bedesirable to increase the level of ATP in that subject to a level abovethe normal level of ATP in that subject. Enhancement can also be ofbeneficial effect in a subject suffering from a disease or pathologysuch as a mitochondrial disease, in that normalizing an energy biomarkermay not achieve the optimum outcome for the subject; in such cases,enhancement of one or more energy biomarkers can be beneficial, forexample, higher-than-normal levels of ATP, or lower-than-normal levelsof lactic acid (lactate) can be beneficial to such a subject.

By modulating, normalizing, or enhancing the energy biomarker Coenzyme Qis meant modulating, normalizing, or enhancing the variant or variantsof Coenzyme Q which is predominant in the species of interest. Forexample, the variant of Coenzyme Q which predominates in humans isCoenzyme Q10. If a species or subject has more than one variant ofCoenzyme Q present in significant amounts (i.e., present in amountswhich, when modulated, normalized, or enhanced, can have a beneficialeffect on the species or subject), modulating, normalizing, or enhancingCoenzyme Q can refer to modulating, normalizing or enhancing any or allvariants of Coenzyme Q present in the species or subject.

While the compounds described herein can occur and can be used as theneutral (non-salt) compound, the description is intended to embrace allsalts of the compounds described herein, as well as methods of usingsuch salts of the compounds. In one embodiment, the salts of thecompounds comprise pharmaceutically acceptable salts. Pharmaceuticallyacceptable salts are those salts which can be administered as drugs orpharmaceuticals to humans and/or animals and which, upon administration,retain at least some of the biological activity of the free compound(neutral compound or non-salt compound). The desired salt of a basiccompound may be prepared by methods known to those of skill in the artby treating the compound with an acid. Examples of inorganic acidsinclude, but are not limited to, hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, and phosphoric acid. Examples of organicacids include, but are not limited to, formic acid, acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, andsalicylic acid. Salts of basic compounds with amino acids, such asaspartate salts and glutamate salts, can also be prepared. The desiredsalt of an acidic compound can be prepared by methods known to those ofskill in the art by treating the compound with a base. Examples ofinorganic salts of acid compounds include, but are not limited to,alkali metal and alkaline earth salts, such as sodium salts, potassiumsalts, magnesium salts, and calcium salts; ammonium salts; and aluminumsalts. Examples of organic salts of acid compounds include, but are notlimited to, procaine, dibenzylamine, N-ethylpiperidine,N,N-dibenzylethylenediamine, and triethylamine salts. Salts of acidiccompounds with amino acids, such as lysine salts, can also be prepared.

The invention also includes all possible stereoisomers of the compounds,including diastereomers and enantiomers. The invention also includesmixtures of stereoisomers in any ratio, including, but not limited to,racemic mixtures. Unless stereochemistry is explicitly indicated in astructure, the structure is intended to embrace all possiblestereoisomers of the compound depicted. If stereochemistry is explicitlyindicated for one portion or portions of a molecule, but not for anotherportion or portions of a molecule, the structure is intended to embraceall possible stereoisomers for the portion or portions wherestereochemistry is not explicitly indicated.

The compounds can be administered in prodrug form. Prodrugs arederivatives of the compounds which are themselves relatively inactive,but which convert into the active compound when introduced into thesubject in which they are used, by a chemical or biological process invivo, such as an enzymatic conversion. Suitable prodrug formulationsinclude, but are not limited to, peptide conjugates of the compounds ofthe invention and esters of compounds of the inventions. Furtherdiscussion of suitable prodrugs is provided in H. Bundgaard, Design ofProdrugs, New York: Elsevier, 1985; in R. Silverman, The OrganicChemistry of Drug Design and Drug Action, Boston: Elsevier, 2004; in R.L. Juliano (ed.), Biological Approaches to the Controlled Delivery ofDrugs (Annals of the New York Academy of Sciences, v. 507), New York:New York Academy of Sciences, 1987; and in E. B. Roche (ed.), Design ofBiopharmaceutical Properties Through Prodrugs and Analogs (Symposiumsponsored by Medicinal Chemistry Section, APhA Academy of PharmaceuticalSciences, November 1976 national meeting, Orlando, Fla.), Washington:The Academy, 1977.

Metabolites of the compounds are also embraced by the invention.

“(C₁-C₆)-alkyl” is intended to embrace saturated linear, branched, orcyclic groups, or a combination of linear and/or branched and/or cyclichydrocarbon chain and/or ring having 1 to 6 carbon atoms. Examples of“(C₁-C₆)-alkyl” are methyl, ethyl, n-propyl, isopropyl, cyclopropyl,n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, cyclopropyl-methyl,methyl-cyclopropyl, pentyl where the point of attachment of the pentylgroup to the remainder of the molecule can be at any location on thepentyl fragment, cyclopentyl, hexyl where the point of attachment of thehexyl group to the remainder of the molecule can be at any location onthe hexyl fragment, and cyclohexyl. This term may encompass divalenthydrocarbon chains, i.e. (C₁-C₆)-alkylene chains of 1 to 6 carbon atoms.“(C₁-C₄)-alkyl” is intended to embrace saturated linear, branched, orcyclic groups, or a combination of linear and/or branched and/or cyclichydrocarbon chains and/or rings having 1 to 4 carbon atoms.

“(C₁-C₆)-alkylene” is intended to embrace divalent saturated linear,branched, cyclic groups, or a combination thereof having 1 to 6 carbonatoms. Examples of “(C₁-C₆)-alkylene” are, but are not limited to,—CH₂—, —(CH₂)₂—, —CH(CH₃)—, —CH(CH₃)—, —(CH₂)₃—, —CH₂—CH(CH₃)—CH₂—,—CH₂—C(CH₃)₂—CH₂—, —CH₂—CH₂—CH(CH₃)—, —CH₂—CH₂—C(CH₃)₂—, —(CH₂)₄—,—(CH₂)—, —(CH₂)₆—, —(CH₂)₂-cyclopropyl-, -, —(CH₂)₂-cyclobutyl-.“(C₁-C₄)-alkylene” is intended to embrace divalent saturated linear,branched, or cyclic groups, or a combination thereof having 1 to 4carbon atoms.

“(C₂-C₆)-alkenyl” is intended to embrace an unsaturated linear,branched, cyclic, groups or a combination thereof having 2 to 6 carbonatoms. All double bonds may be independently either (E) or (Z) geometry,as well as arbitrary mixtures thereof. Examples of alkenyl groupsinclude, but are not limited to —CH₂—CH═CH—CH₃; and —CH₂-cyclopentenyl,where the methylene group can be attached to the cyclopentyl moiety atany available carbon valence. “(C₂-C₄)-alkenyl” is intended to embraceunsaturated linear or branched groups or a combination thereof having 2to 4 carbon atoms.

“(C₂-C₆)-alkenylene” is intended to embrace divalent unsaturated linear,branched, cyclic, groups or a combination thereof having 2 to 6 carbonatoms. “(C₂-C₄)-alkenylene” is intended to embrace divalent unsaturatedlinear or branched groups or a combination thereof having 2 to 4 carbonatoms.

“(C₂-C₆)-alkynyl” is intended to embrace an unsaturated linear,branched, cyclic, groups or a combination thereof having 2 to 6 carbonatoms, which contain at least one triple bond. “(C₂-C₄)-alkynyl” isintended to embrace unsaturated linear or branched groups or acombination thereof having 2 to 4 carbon atoms, which contain at leastone triple bond.

“(C₂-C₆)-alkynylene” is intended to embrace a divalent unsaturatedlinear, branched, cyclic, groups or a combination thereof having 2 to 6carbon atoms, which contain at least one triple bond.“(C₂-C₄)-alkynylene” is intended to embrace divalent unsaturated linearor branched groups or a combination thereof having 2 to 4 carbon atoms,which contain at least one triple bond.

“Halogen” or “halo” designates fluoro (—F), chloro (—Cl), bromo (—Br),and iodo (—I).

“(C₁-C₆)-haloalkyl” is intended to embrace any (C₁-C₆)-alkyl substituenthaving at least one halogen substituent; the halogen can be attached viaany valence on the (C₁-C₆)-alkyl group. One subset of (C₁-C₆)haloalkylis —CF₃, —CCl₃, —CBr₃, and —CI₃. Another subset of (C₁-C₆)-haloalkyl is—CHF₂, —CHCl₂, —CHBr₂, and —CHI₂. Another subset of (C₁-C₆)-haloalkyl is—CH₂F, —CH₂Cl, —CH₂Br, and —CH₂I. Another subset of (C₁-C₆)-haloalkyl isthe subset of (C₁-C₆)-perhaloalkyls where all available valences arereplaced by halogens. Another subset of (C₁-C₆)-haloalkyl is the subsetof (C₁-C₆)-perfluoroalkyl; where all available valences are replaced byfluorine atoms. Another subset of (C₁-C₆)-haloalkyl is the subset of(C₁-C₆)-perchloroalkyl; that is, (C₁-C₆)-alkyl with all availablevalences replaced by chlorine atoms.

The term “aryl” is intended to embrace an aromatic cyclic hydrocarbongroup of from 6 to 20 carbon atoms having a single ring (e.g., phenyl)or multiple condensed (fused) rings (e.g., naphthyl or anthryl).

The term “Friedreich's ataxia” is intended to embrace other ataxias, andis also sometimes referred to as hereditary ataxia, familiar ataxia, orFriedreich's tabes.

The term “Ataxia” is an aspecific clinical manifestation implyingdysfunction of parts of the nervous system that coordinate movement,such as the cerebellum. People with ataxia have problems withcoordination because parts of the nervous system that control movementand balance are affected. Ataxia may affect the fingers, hands, arms,legs, body, speech, and eye movements. The word ataxia is often used todescribe a symptom of incoordination which can be associated withinfections, injuries, other diseases, or degenerative changes in thecentral nervous system. Ataxia is also used to denote a group ofspecific degenerative diseases of the nervous system called thehereditary and sporadic ataxias. Ataxias are also often associated withhearing impairments.

There are three types of ataxia, cerebellar ataxia, includingvestibulo-cerebellar dysfunction, spino-cerebellar dysfunction, andcerebro-cerebellar dysfunction; Sensory ataxia and Vestibular ataxia.Examples of the diseases which are classifiable into spino-cerebellarataxia or multiple system atrophy are hereditary olivo-ponto-cerebellaratrophy, hereditary cerebellar cortical atrophy, Friedreich's ataxia,Machado-Joseph diseases, Ramsay Hunt syndrome, hereditarydentatorubral-pallidoluysian atrophy, hereditary spastic paraplegia,Shy-Drager syndrome, cortical cerebellar atrophy, striato-nigraldegeneration, Marinesco-Sjogren syndrome, alcoholic cortical cerebellaratrophy, paraneoplasic cerebellar atrophy associated with malignanttumor, toxic cerebellar atrophy caused by toxic substances, cerebellaratrophy associated with endocrine disturbance and the like.

Examples of ataxia symptoms are motor ataxia, trunk ataxia, limb ataxiaand the like, autonomic disturbance such as orthostatic hypotension,dysuria, hypohidrosis, sleep apnea, orthostatic syncope and the like,stiffness of lower extremity, ocular nystagmus, oculomotor nervedisorder, pyramidal tract dysfunction, extra pyramidal symptom (posturaladjustment dysfunction, muscular rigidity, akinesia, tremulus),dysphagia, lingual atrophy, posterior funiculus symptom, muscle atrophy,muscle weakness, deep hyperreflexia, sensory disturbance, scoliosis,kyphoscoliosis, foot deformans, anarthria, dementia, manic state,decreased motivation for rehabilitation and the like.

The terms “heterocycle”, “heterocyclic”, “heterocyclo”, and“heterocyclyl” is intended to encompass a monovalent, saturated,partially unsaturated, or unsaturated (heteroaryl) carbocyclic radicalhaving one or more rings incorporating one, two, three or fourheteroatoms within the ring (chosen from nitrogen, oxygen, and/orsulfur). Examples of heterocycles include morpholine, piperidine,piperazine, thiazolidine, dithiolane, pyrazolidine, pyrazoline,imidazolidine, pyrrolidine, tetrahydropyran, tetrahydrofuran,quinuclidine, pyridine, pyrazine, imidazoline, thiazole, isothiazole,pyrazine, triazine, pyrimidine, pyridazine, pyrazole, thiophene,pyrrole, pyran, furan, indole, quinoline, quinazoline, benzodioxole,benzimidazole, benzothiophene, benzofuran, benzoxazole, benzothiazole,benzotriazole, imidazo-pyridines, pyrazolo-pyridines, pyrazolo-pyrazine,acridine, carbazole, and the like.

The terms “Parkinson's”, (also called “Parkinsonism” and “Parkinsoniansyndrome”) (“PD”) is intended to include not only Parkinson's diseasebut also drug-induced Parkinsonism and post-encephalitic Parkinsonism.Parkinson's disease is also known as paralysis agitans or shaking palsy.It is characterized by tremor, muscular rigidity and loss of posturalreflexes. The disease usually progresses slowly with intervals of 10 to20 years elapsing before the symptoms cause incapacity. Due to theirmimicry of effects of Parkinson's disease, treatment of animals withmethamphetamine or MPTP has been used to generate models for Parkinson'sdisease. These animal models have been used to evaluate the efficacy ofvarious therapies for Parkinson's disease.

In general, the nomenclature used in this application was generated withthe help of naming package within the ChemOffice® version 11.0 suite ofprograms by CambridgeSoft Corp (Cambridge, Mass.).

Diseases Amenable to Treatment or Suppression with Compounds and Methodsof the Invention

A variety of diseases are believed to be caused or aggravated byoxidative stress affecting normal electron flow in the cells, such asmitochondrial disorders, impaired energy processing disorder,neurodegenerative diseases and diseases of aging, and can be treated orsuppressed using the compounds and methods of the invention. Suchdiseases include, but are not limited to, inherited mitochondrialdiseases, such as Myoclonic Epilepsy with Ragged Red Fibers (MERRF),Mitochondrial Myopathy, Encephalopathy, Lactacidosis, Stroke (MELAS),Maternally Inherited Diabetes and Deafness (MIDD), Leber's HereditaryOptic Neuropathy (LHON, also referred to as Leber's Disease, Leber'sOptic Atrophy (LOA), or Leber's Optic Neuropathy (LON)), Leigh Diseaseor Leigh Syndrome, Kearns-Sayre Syndrome (KSS), Friedreich's Ataxia(FRDA), Co-Enzyme Q10 (CoQ10) deficiency; other myopathies (includingcardiomyopathy and encephalomyopathy), and renal tubular acidosis;neurodegenerative diseases, such as Parkinson's disease, Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig'sdisease), motor neuron diseases; hearing and balance impairmentdiseases; other neurological diseases such as epilepsy; genetic diseasessuch as Huntington's Disease (which is also a neurological disease);mood disorders such as schizophrenia and bipolar disorder; and certainage-associated diseases, particularly diseases for which CoQ10 has beenproposed for treatment, such as macular degeneration, diabetes, andcancer. Mitochondrial dysfunction is also implicated in excitoxic,neuronal injury, such as that associated with seizures and ischemia.Mitochondrial dysfunction is also implicated in pervasive developmentdisorders such as Autistic Disorder, Asperger's Disorder, ChildhoodDisintegrative Disorder (CDD), Rett's Disorder, and PDD-Not OtherwiseSpecified (PDD-NOS). Diseases caused by energy impairment includediseases due to deprivation, poisoning or toxicity of oxygen, andqualitative or quantitative disruption in the transport of oxygen suchas haemaglobionopathies for example thalassemia or sickle cell anemia.

Clinical Assessment of Mitochondrial Dysfunction and Efficacy of Therapy

Several readily measurable clinical markers are used to assess themetabolic state of patients with mitochondrial disorders or impairedenergy processing disorders. These markers can also be used asindicators of the efficacy of a given therapy, as the level of a markeris moved from the pathological value to the healthy value. Theseclinical markers include, but are not limited to, one or more of thepreviously discussed energy biomarkers, such as lactic acid (lactate)levels, either in whole blood, plasma, cerebrospinal fluid, or cerebralventricular fluid; pyruvic acid (pyruvate) levels, either in wholeblood, plasma, cerebrospinal fluid, or cerebral ventricular fluid;lactate/pyruvate ratios, either in whole blood, plasma, cerebrospinalfluid, or cerebral ventricular fluid; phosphocreatine levels, NADH(NADH+H⁺) or NADPH (NADPH+H⁺) levels; NAD or NADP levels; ATP levels;anaerobic threshold; reduced coenzyme Q (CoQ^(red)) levels; oxidizedcoenzyme Q (CoQ^(ox)) levels; total coenzyme Q (CoQ^(tot)) levels;oxidized cytochrome C levels; reduced cytochrome C levels; oxidizedcytochrome C/reduced cytochrome C ratio; acetoacetate levels, β-hydroxybutyrate levels, acetoacetate/β-hydroxy butyrate ratio,8-hydroxy-β′-deoxyguanosine (8-OHdG) levels; levels of reactive oxygenspecies; and levels of oxygen consumption (VO2), levels of carbondioxide output (VCO2), and respiratory quotient (VCO2/VO2). Several ofthese clinical markers are measured routinely in exercise physiologylaboratories, and provide convenient assessments of the metabolic stateof a subject. In one embodiment of the invention, the level of one ormore energy biomarkers in a patient suffering from a mitochondrialdisease, such as Friedreich's ataxia, Leber's hereditary opticneuropathy, MELAS, MIDD, or KSS, is improved to within two standarddeviations of the average level in a healthy subject. In anotherembodiment of the invention, the level of one or more of these energybiomarkers in a patient suffering from a mitochondrial disease, such asFriedreich's ataxia, Leber's hereditary optic neuropathy, MELAS, MIDD,or KSS is improved to within one standard deviation of the average levelin a healthy subject. Exercise intolerance can also be used as anindicator of the efficacy of a given therapy, where an improvement inexercise tolerance (i.e., a decrease in exercise intolerance) indicatesefficacy of a given therapy.

Several metabolic biomarkers have already been used to evaluate efficacyof CoQ10, and these metabolic biomarkers can be monitored as energybiomarkers for use in the methods of the current invention. Pyruvate, aproduct of the anaerobic metabolism of glucose, is removed by reductionto lactic acid in an anaerobic setting or by oxidative metabolism, whichis dependent on a functional mitochondrial respiratory chain.Dysfunction of the respiratory chain may lead to inadequate removal oflactate and pyruvate from the circulation and elevated lactate/pyruvateratios are observed in mitochondrial cytopathies (see Scriver C R, Themetabolic and molecular bases of inherited disease, 7th ed., New York:McGraw-Hill, Health Professions Division, 1995; and Munnich et al., J.Inherit. Metab. Dis. 15(4):448-55 (1992)). Blood lactate/pyruvate ratio(Chariot et al., Arch. Pathol. Lab. Med. 118(7):695-7 (1994)) is,therefore, widely used as a noninvasive test for detection ofmitochondrial cytopathies (see again Scriver C R, The metabolic andmolecular bases of inherited disease, 7th ed., New York: McGraw-Hill,Health Professions Division, 1995; and Munnich et al., J. Inherit.Metab. Dis. 15(4):448-55 (1992)) and toxic mitochondrial myopathies(Chariot et al., Arthritis Rheum. 37(4):583-6 (1994)). Changes in theredox state of liver mitochondria can be investigated by measuring thearterial ketone body ratio (acetoacetate/3-hydroxybutyrate: AKBR) (Uedaet al., J. Cardiol. 29(2):95-102 (1997)). Urinary excretion of8-hydroxy-2′-deoxyguanosine (8-OHdG) often has been used as a biomarkerto assess the extent of repair of ROS-induced DNA damage in bothclinical and occupational settings (Erhola et al., FEBS Lett.409(2):287-91 (1997); Honda et al., Leuk. Res. 24(6):461-8 (2000);Pilger et al., Free Radic. Res. 35(3):273-80 (2001); Kim et al. EnvironHealth Perspect 112(6):666-71 (2004)).

Magnetic resonance spectroscopy (MRS) has been useful in the diagnosesof mitochondrial cytopathy by demonstrating elevations in cerebrospinalfluid (CSF) and cortical white matter lactate using proton MRS (1H-MRS)(Kaufmann et al., Neurology 62(8):1297-302 (2004)). Phosphorous MRS(31P-MRS) has been used to demonstrate low levels of corticalphosphocreatine (PCr) (Matthews et al., Ann. Neurol. 29(4):435-8(1991)), and a delay in PCr recovery kinetics following exercise inskeletal muscle (Matthews et al., Ann. Neurol. 29(4):435-8 (1991);Barbiroli et al., J. Neurol. 242(7):472-7 (1995); Fabrizi et al., J.Neurol. Sci. 137(1):20-7 (1996)). A low skeletal muscle PCr has alsobeen confirmed in patients with mitochondrial cytopathy by directbiochemical measurements.

Exercise testing is particularly helpful as an evaluation and screeningtool in mitochondrial myopathies. One of the hallmark characteristics ofmitochondrial myopathies is a reduction in maximal whole body oxygenconsumption (VO2max) (Taivassalo et al., Brain 126(Pt 2):413-23 (2003)).Given that VO2max is determined by cardiac output (Qc) and peripheraloxygen extraction (arterial-venous total oxygen content) difference,some mitochondrial cytopathies affect cardiac function where deliverycan be altered; however, most mitochondrial myopathies show acharacteristic deficit in peripheral oxygen extraction (A-VO2difference) and an enhanced oxygen delivery (hyperkinetic circulation)(Taivassalo et al., Brain 126(Pt 2):413-23 (2003)). This can bedemonstrated by a lack of exercise induced deoxygenation of venous bloodwith direct AV balance measurements (Taivassalo et al., Ann. Neurol.51(1):38-44 (2002)) and non-invasively by near infrared spectroscopy(Lynch et al., Muscle Nerve 25(5):664-73 (2002); van Beekvelt et al.,Ann. Neurol. 46(4):667-70 (1999)).

Several of these energy biomarkers are discussed in more detail asfollows. It should be emphasized that, while certain energy biomarkersare discussed and enumerated herein, the invention is not limited tomodulation, normalization or enhancement of only these enumerated energybiomarkers.

Lactic Acid (Lactate) Levels: Mitochondrial dysfunction typicallyresults in abnormal levels of lactic acid, as pyruvate levels increaseand pyruvate is converted to lactate to maintain capacity forglycolysis. Mitochondrial dysfunction can also result in abnormal levelsof NADH+H⁺, NADPH+H⁺, NAD, or NADP, as the reduced nicotinamide adeninedinucleotides are not efficiently processed by the respiratory chain.Lactate levels can be measured by taking samples of appropriate bodilyfluids such as whole blood, plasma, or cerebrospinal fluid. Usingmagnetic resonance, lactate levels can be measured in virtually anyvolume of the body desired, such as the brain.

Measurement of cerebral lactic acidosis using magnetic resonance inMELAS patients is described in Kaufmann et al., Neurology 62(8): 1297(2004). Values of the levels of lactic acid in the lateral ventricles ofthe brain are presented for two mutations resulting in MELAS, A3243G andA8344G. Whole blood, plasma, and cerebrospinal fluid lactate levels canbe measured by commercially available equipment such as the YSI 2300STAT Plus Glucose & Lactate Analyzer (YSI Life Sciences, Ohio).

NAD, NADP, NADH and NADPH Levels: Measurement of NAD, NADP, NADH(NADH+H⁺) or NADPH (NADPH+H⁺) can be measured by a variety offluorescent, enzymatic, or electrochemical techniques, e.g., theelectrochemical assay described in US 2005/0067303.

Oxygen Consumption (vO₂ or VO2), Carbon Dioxide Output (vCO₂ or VCO2),and Respiratory Quotient (VCO2/VO2): vO₂ is usually measured eitherwhile resting (resting vO₂) or at maximal exercise intensity (vO₂ max).Optimally, both values will be measured. However, for severely disabledpatients, measurement of vO₂ max may be impractical. Measurement of bothforms of vO₂ is readily accomplished using standard equipment from avariety of vendors, e.g. Korr Medical Technologies, Inc. (Salt LakeCity, Utah). VCO2 can also be readily measured, and the ratio of VCO2 toVO2 under the same conditions (VCO2/VO2, either resting or at maximalexercise intensity) provides the respiratory quotient (RQ).

Oxidized Cytochrome C, Reduced Cytochrome C, and Ratio of OxidizedCytochrome C to Reduced Cytochrome C: Cytochrome C parameters, such asoxidized cytochrome C levels (Cyt C_(ox)), reduced cytochrome C levels(Cyt C_(red)), and the ratio of oxidized cytochrome C/reduced cytochromeC ratio (Cyt C_(ox))/(Cyt C_(red)), can be measured by in vivo nearinfrared spectroscopy. See, e.g., Rolfe, P., “In vivo near-infraredspectroscopy,” Ann. Rev. Biomed. Eng. 2:715-54 (2000) and Strangman etal., “Non-invasive neuroimaging using near-infrared light” Biol.Psychiatry 52:679-93 (2002).

Exercise Tolerance/Exercise Intolerance: Exercise intolerance is definedas “the reduced ability to perform activities that involve dynamicmovement of large skeletal muscles because of symptoms of dyspnoea orfatigue” (Piña et al., Circulation 107:1210 (2003)). Exerciseintolerance is often accompanied by myoglobinuria, due to breakdown ofmuscle tissue and subsequent excretion of muscle myoglobin in the urine.Various measures of exercise intolerance can be used, such as time spentwalking or running on a treadmill before exhaustion, time spent on anexercise bicycle (stationary bicycle) before exhaustion, and the like.Treatment with the compounds or methods of the invention can result inabout a 10% or greater improvement in exercise tolerance (for example,about a 10% or greater increase in time to exhaustion, e.g. from 10minutes to 11 minutes), about a 20% or greater improvement in exercisetolerance, about a 30% or greater improvement in exercise tolerance,about a 40% or greater improvement in exercise tolerance, about a 50% orgreater improvement in exercise tolerance, about a 75% or greaterimprovement in exercise tolerance, or about a 100% or greaterimprovement in exercise tolerance. While exercise tolerance is not,strictly speaking, an energy biomarker, for the purposes of theinvention, modulation, normalization, or enhancement of energybiomarkers includes modulation, normalization, or enhancement ofexercise tolerance.

Similarly, tests for normal and abnormal values of pyruvic acid(pyruvate) levels, lactate/pyruvate ratio, ATP levels, anaerobicthreshold, reduced coenzyme Q (CoQ^(red)) levels, oxidized coenzyme Q(CoQ^(ox)) levels, total coenzyme Q (CoQ^(tot)) levels, oxidizedcytochrome C levels, reduced cytochrome C levels, oxidized cytochromeC/reduced cytochrome C ratio, acetoacetate levels, β-hydroxy butyratelevels, acetoacetate/β-hydroxy butyrate ratio,8-hydroxy-2′-deoxyguanosine (8-OHdG) levels, and levels of reactiveoxygen species are known in the art and can be used to evaluate efficacyof the compounds and methods of the invention. (For the purposes of theinvention, modulation, normalization, or enhancement of energybiomarkers includes modulation, normalization, or enhancement ofanaerobic threshold.)

Table 1, following, illustrates the effect that various dysfunctions canhave on biochemistry and energy biomarkers. It also indicates thephysical effect (such as a disease symptom or other effect of thedysfunction) typically associated with a given dysfunction. It should benoted that any of the energy biomarkers listed in the table, in additionto energy biomarkers enumerated elsewhere, can also be modulated,enhanced, or normalized by the compounds and methods of the invention.RQ=respiratory quotient; BMR=basal metabolic rate; HR (CO)=heart rate(cardiac output); T=body temperature (preferably measured as coretemperature); AT=anaerobic threshold; pH=blood pH (venous and/orarterial).

TABLE 1 Site of Biochemical Measurable Dysfunction Event EnergyBiomarker Physical Effect Respiratory ↑ NADH Δ lactate, Metabolic ChainΔ lactate: pyruvate dyscrasia & ratio; and fatigue Δ acetoacetate:β-hydroxy butyrate ratio Respiratory ↓ H⁺ gradient Δ ATP Organ dependentChain dysfunction Respiratory ↓ Electron flux Δ VO₂, RQ, BMR, MetabolicChain ΔT, AT, pH dyscrasia & fatigue Mitochondria & ↓ ATP, ↓ VO₂ Δ Work,Δ HR (CO) Exercise cytosol intolerance Mitochondria & ↓ ATP Δ PCrExercise cytosol intolerance Respiratory ↓ Cyt C_(Ox/Red) Δ λ~700-900 nMExercise Chain (Near Infrared intolerance Spectroscopy) Intermediary ↓Catabolism Δ C¹⁴-Labeled Metabolic metabolism substrates dyscrasia &fatigue Respiratory ↓ Electron flux Δ Mixed Venous Metabolic Chain VO₂dyscrasia & fatigue Mitochondria & ↑ Oxidative Δ Tocopherol & Uncertaincytosol stress Tocotrienols, CoQ10, docosahexanoic acid Mitochondria & ↑Oxidative Δ Glutathione_(red) Uncertain cytosol stress Mitochondria &Nucleic acid Δ8-hydroxy Uncertain cytosol oxidation 2-deoxy guanosineMitochondria & Lipid oxidation Δ Isoprostane(s), Uncertain cytosoleicasanoids Cell membranes Lipid oxidation Δ Ethane (breath) UncertainCell membranes Lipid oxidation Δ Malondialdehyde Uncertain

Treatment of a subject afflicted by a mitochondrial disease inaccordance with the methods of the invention may result in theinducement of a reduction or alleviation of symptoms in the subject,e.g., to halt the further progression of the disorder.

Partial or complete suppression of the mitochondrial disease can resultin a lessening of the severity of one or more of the symptoms that thesubject would otherwise experience. For example, partial suppression ofMELAS could result in reduction in the number of stroke-like or seizureepisodes suffered.

Any one or any combination of the energy biomarkers described hereinprovides conveniently measurable benchmarks by which to gauge theeffectiveness of treatment or suppressive therapy. Additionally, otherenergy biomarkers are known to those skilled in the art and can bemonitored to evaluate the efficacy of treatment or suppressive therapy.

Use of Compounds for Modulation of Energy Biomarkers

In addition to monitoring energy biomarkers to assess the status oftreatment or suppression of mitochondrial diseases or impaired energyprocessing disorders, the compounds of the invention can be used insubjects or patients to modulate one or more energy biomarkers.Modulation of energy biomarkers can be done to normalize energybiomarkers in a subject, or to enhance energy biomarkers in a subject.

Normalization of one or more energy biomarkers is defined as eitherrestoring the level of one or more such energy biomarkers to normal ornear-normal levels in a subject whose levels of one or more energybiomarkers show pathological differences from normal levels (i.e.,levels in a healthy subject), or to change the levels of one or moreenergy biomarkers to alleviate pathological symptoms in a subject.Depending on the nature of the energy biomarker, such levels may showmeasured values either above or below a normal value. For example, apathological lactate level is typically higher than the lactate level ina normal (i.e., healthy) person, and a decrease in the level may bedesirable. A pathological ATP level is typically lower than the ATPlevel in a normal (i.e., healthy) person, and an increase in the levelof ATP may be desirable. Accordingly, normalization of energy biomarkerscan involve restoring the level of energy biomarkers to within about atleast two standard deviations of normal in a subject, more preferably towithin about at least one standard deviation of normal in a subject, towithin about at least one-half standard deviation of normal, or towithin about at least one-quarter standard deviation of normal.

Enhancement of the level of one or more energy biomarkers is defined aschanging the extant levels of one or more energy biomarkers in a subjectto a level which provides beneficial or desired effects for the subject.For example, a person undergoing strenuous effort or prolonged vigorousphysical activity, such as mountain climbing, could benefit fromincreased ATP levels or decreased lactate levels. As described above,normalization of energy biomarkers may not achieve the optimum state fora subject with a mitochondrial disease, and such subjects can alsobenefit from enhancement of energy biomarkers. Examples of subjects whocould benefit from enhanced levels of one or more energy biomarkersinclude, but are not limited to, subjects undergoing strenuous orprolonged physical activity, subjects with chronic energy problems, orsubjects with chronic respiratory problems. Such subjects include, butare not limited to, pregnant females, particularly pregnant females inlabor; neonates, particularly premature neonates; subjects exposed toextreme environments, such as hot environments (temperatures routinelyexceeding about 85-86 degrees Fahrenheit or about 30 degrees Celsius forabout 4 hours daily or more), cold environments (temperatures routinelybelow about 32 degrees Fahrenheit or about 0 degrees Celsius for about 4hours daily or more), or environments with lower-than-average oxygencontent, higher-than-average carbon dioxide content, orhigher-than-average levels of air pollution (airline travelers, flightattendants, subjects at elevated altitudes, subjects living in citieswith lower-than-average air quality, subjects working in enclosedenvironments where air quality is degraded); subjects with lung diseasesor lower-than-average lung capacity, such as tubercular patients, lungcancer patients, emphysema patients, and cystic fibrosis patients;subjects recovering from surgery or illness; elderly subjects, includingelderly subjects experiencing decreased energy; subjects suffering fromchronic fatigue, including chronic fatigue syndrome; subjects undergoingacute trauma; subjects in shock; subjects requiring acute oxygenadministration; subjects requiring chronic oxygen administration; orother subjects with acute, chronic, or ongoing energy demands who canbenefit from enhancement of energy biomarkers.

Accordingly, when an increase in a level of one or more energybiomarkers is beneficial to a subject, enhancement of the one or moreenergy biomarkers can involve increasing the level of the respectiveenergy biomarker or energy biomarkers to about at least one-quarterstandard deviation above normal, about at least one-half standarddeviation above normal, about at least one standard deviation abovenormal, or about at least two standard deviations above normal.Alternatively, the level of the one or more energy biomarkers can beincreased by about at least 10% above the subject's level of therespective one or more energy biomarkers before enhancement, by about atleast 20% above the subject's level of the respective one or more energybiomarkers before enhancement, by about at least 30% above the subject'slevel of the respective one or more energy biomarkers beforeenhancement, by about at least 40% above the subject's level of therespective one or more energy biomarkers before enhancement, by about atleast 50% above the subject's level of the respective one or more energybiomarkers before enhancement, by about at least 75% above the subject'slevel of the respective one or more energy biomarkers beforeenhancement, or by about at least 100% above the subject's level of therespective one or more energy biomarkers before enhancement.

When a decrease in a level of one or more energy biomarkers is desiredto enhance one or more energy biomarkers, the level of the one or moreenergy biomarkers can be decreased by an amount of about at leastone-quarter standard deviation of normal in a subject, decreased byabout at least one-half standard deviation of normal in a subject,decreased by about at least one standard deviation of normal in asubject, or decreased by about at least two standard deviations ofnormal in a subject. Alternatively, the level of the one or more energybiomarkers can be decreased by about at least 10% below the subject'slevel of the respective one or more energy biomarkers beforeenhancement, by about at least 20% below the subject's level of therespective one or more energy biomarkers before enhancement, by about atleast 30% below the subject's level of the respective one or more energybiomarkers before enhancement, by about at least 40% below the subject'slevel of the respective one or more energy biomarkers beforeenhancement, by about at least 50% below the subject's level of therespective one or more energy biomarkers before enhancement, by about atleast 75% below the subject's level of the respective one or more energybiomarkers before enhancement, or by about at least 90% below thesubject's level of the respective one or more energy biomarkers beforeenhancement.

Use of Compounds in Research Applications, Experimental Systems, andAssays

The compounds of the invention can also be used in researchapplications. They can be used in vitro, in vivo, or ex vivo experimentsto modulate one or more energy biomarkers in an experimental system.Such experimental systems can be cell samples, tissue samples, cellcomponents or mixtures of cell components, partial organs, whole organs,or organisms. Any one or more of the compounds of the invention can beused in experimental systems or research applications. Such researchapplications can include, but are not limited to, use as assay reagents,elucidation of biochemical pathways, or evaluation of the effects ofother agents on the metabolic state of the experimental system in thepresence/absence of one or more compounds of the invention.

Additionally, the compounds of the invention can be used in biochemicaltests or assays. Such tests can include incubation of one or morecompounds of the invention with a tissue or cell sample from a subjectto evaluate a subject's potential response (or the response of aspecific subset of subjects) to administration of said one or morecompounds, or to determine which compound of the invention produces theoptimum effect in a specific subject or subset of subjects. One suchtest or assay would involve 1) obtaining a cell sample or tissue samplefrom a subject in which modulation of one or more energy biomarkers canbe assayed; 2) administering one or more compounds of the invention tothe cell sample or tissue sample; and 3) determining the amount ofmodulation of the one or more energy biomarkers after administration ofthe one or more compounds, compared to the status of the energybiomarker prior to administration of the one or more compounds. Anothersuch test or assay would involve 1) obtaining a cell sample or tissuesample from a subject in which modulation of one or more energybiomarkers can be assayed; 2) administering at least two compounds ofthe invention to the cell sample or tissue sample; 3) determining theamount of modulation of the one or more energy biomarkers afteradministration of the at least two compounds, compared to the status ofthe energy biomarker prior to administration of the at least compounds;and 4) selecting a compound for use in treatment, suppression, ormodulation based on the amount of modulation determined in step 3).

Pharmaceutical Formulations

The compounds described herein can be formulated as pharmaceuticalcompositions by formulation with additives such as pharmaceuticallyacceptable excipients, pharmaceutically acceptable carriers, andpharmaceutically acceptable vehicles. Suitable pharmaceuticallyacceptable excipients, carriers and vehicles include processing agentsand drug delivery modifiers and enhancers, such as, for example, calciumphosphate, magnesium stearate, talc, monosaccharides, disaccharides,starch, gelatin, cellulose, methyl cellulose, sodium carboxymethylcellulose, dextrose, hydroxypropyl-β-cyclodextrin,polyvinylpyrrolidinone, low melting waxes, ion exchange resins, and thelike, as well as combinations of any two or more thereof. Other suitablepharmaceutically acceptable excipients are described in “Remington'sPharmaceutical Sciences,” Mack Pub. Co., New Jersey (1991), and“Remington: The Science and Practice of Pharmacy,” Lippincott Williams &Wilkins, Philadelphia, 20th edition (2003) and 21st edition (2005),incorporated herein by reference.

A pharmaceutical composition can comprise a unit dose formulation, wherethe unit dose is a dose sufficient to have a therapeutic or suppressiveeffect or an amount effective to modulate, normalize, or enhance anenergy biomarker. The unit dose may be sufficient as a single dose tohave a therapeutic or suppressive effect or an amount effective tomodulate, normalize, or enhance an energy biomarker. Alternatively, theunit dose may be a dose administered periodically in a course oftreatment or suppression of a disorder, or to modulate, normalize, orenhance an energy biomarker.

Pharmaceutical compositions containing the compounds of the inventionmay be in any form suitable for the intended method of administration,including, for example, a solution, a suspension, or an emulsion. Liquidcarriers are typically used in preparing solutions, suspensions, andemulsions. Liquid carriers contemplated for use in the practice of thepresent invention include, for example, water, saline, pharmaceuticallyacceptable organic solvent(s), pharmaceutically acceptable oils or fats,and the like, as well as mixtures of two or more thereof. The liquidcarrier may contain other suitable pharmaceutically acceptable additivessuch as solubilizers, emulsifiers, nutrients, buffers, preservatives,suspending agents, thickening agents, viscosity regulators, stabilizers,and the like. Suitable organic solvents include, for example, monohydricalcohols, such as ethanol, and polyhydric alcohols, such as glycols.Suitable oils include, for example, soybean oil, coconut oil, olive oil,safflower oil, cottonseed oil, and the like. For parenteraladministration, the carrier can also be an oily ester such as ethyloleate, isopropyl myristate, and the like. Compositions of the presentinvention may also be in the form of microparticles, microcapsules,liposomal encapsulates, and the like, as well as combinations of any twoor more thereof.

Time-release or controlled release delivery systems may be used, such asa diffusion controlled matrix system or an erodible system, as describedfor example in: Lee, “Diffusion-Controlled Matrix Systems”, pp. 155-198and Ron and Langer, “Erodible Systems”, pp. 199-224, in “Treatise onControlled Drug Delivery”, A. Kydonieus Ed., Marcel Dekker, Inc., NewYork 1992. The matrix may be, for example, a biodegradable material thatcan degrade spontaneously in situ and in vivo for, example, byhydrolysis or enzymatic cleavage, e.g., by proteases. The deliverysystem may be, for example, a naturally occurring or synthetic polymeror copolymer, for example in the form of a hydrogel. Exemplary polymerswith cleavable linkages include polyesters, polyorthoesters,polyanhydrides, polysaccharides, poly(phosphoesters), polyamides,polyurethanes, poly(imidocarbonates) and poly(phosphazenes).

The compounds of the invention may be administered enterally, orally,parenterally, sublingually, by inhalation (e.g. as mists or sprays),rectally, or topically in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvants,and vehicles as desired. For example, suitable modes of administrationinclude oral, subcutaneous, transdermal, transmucosal, iontophoretic,intravenous, intraarterial, intramuscular, intraperitoneal, intranasal(e.g. via nasal mucosa), intraocular, subdural, rectal,gastrointestinal, and the like, and directly to a specific or affectedorgan or tissue. For delivery to the central nervous system, spinal andepidural administration, or administration to cerebral ventricles, canbe used. Topical administration may also involve the use of transdermaladministration such as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques. The compounds are mixed with pharmaceutically acceptablecarriers, adjuvants, and vehicles appropriate for the desired route ofadministration. Oral administration is a preferred route ofadministration, and formulations suitable for oral administration arepreferred formulations. The compounds described for use herein can beadministered in solid form, in liquid form, in aerosol form, or in theform of tablets, pills, powder mixtures, capsules, granules,injectables, creams, solutions, suppositories, enemas, colonicirrigations, emulsions, dispersions, food premixes, and in othersuitable forms. The compounds can also be administered in liposomeformulations. The compounds can also be administered as prodrugs, wherethe prodrug undergoes transformation in the treated subject to a formwhich is therapeutically effective. Additional methods of administrationare known in the art.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in propylene glycol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may also compriseadditional substances other than inert diluents, e.g., lubricatingagents such as magnesium stearate. In the case of capsules, tablets, andpills, the dosage forms may also comprise buffering agents. Tablets andpills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, cyclodextrins, and sweetening,flavoring, and perfuming agents.

The compounds of the present invention can also be administered in theform of liposomes. As is known in the art, liposomes are generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono- or multilamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and metabolizable lipid capable of forming liposomes can beused. The present compositions in liposome form can contain, in additionto a compound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natural and synthetic. Methodsto form liposomes are known in the art. See, for example, Prescott, Ed.,Methods in Cell Biology, Volume XIV, Academic Press, New York, N.W., p.33 et seq (1976).

The invention also provides articles of manufacture and kits containingmaterials useful for treating or suppressing oxidative stress diseasesaffecting normal electron flow in the cells, such as mitochondrialdiseases, impaired energy processing disorders, neurodegenerativedisorders and diseases of aging. The invention also provides kitscomprising any one or more of the compounds of the invention. In someembodiments, the kit of the invention comprises the container describedabove.

In other aspects, the kits may be used for any of the methods describedherein, including, for example, to treat an individual with amitochondrial disorder, or to suppress a mitochondrial disorder in anindividual.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost to which the active ingredient is administered and the particularmode of administration. It will be understood, however, that thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, body area, body mass index (BMI),general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination, and the type,progression, and severity of the particular disease undergoing therapy.The pharmaceutical unit dosage chosen is usually fabricated andadministered to provide a defined final concentration of drug in theblood, tissues, organs, or other targeted region of the body. Thetherapeutically effective amount or effective amount for a givensituation can be readily determined by routine experimentation and iswithin the skill and judgment of the ordinary clinician.

Examples of dosages which can be used are an effective amount within thedosage range of about 0.1 mg/kg to about 300 mg/kg body weight, orwithin about 1.0 mg/kg to about 100 mg/kg body weight, or within about1.0 mg/kg to about 50 mg/kg body weight, or within about 1.0 mg/kg toabout 30 mg/kg body weight, or within about 1.0 mg/kg to about 10 mg/kgbody weight, or within about 10 mg/kg to about 100 mg/kg body weight, orwithin about 50 mg/kg to about 150 mg/kg body weight, or within about100 mg/kg to about 200 mg/kg body weight, or within about 150 mg/kg toabout 250 mg/kg body weight, or within about 200 mg/kg to about 300mg/kg body weight, or within about 250 mg/kg to about 300 mg/kg bodyweight. Compounds of the present invention may be administered in asingle daily dose, or the total daily dosage may be administered individed dosage of two, three or four times daily.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more other agents used in the treatment or suppression ofdisorders. Representative agents useful in combination with thecompounds of the invention for the treatment or suppression ofmitochondrial diseases include, but are not limited to, Coenzyme Q,vitamin E, Idebenone, MitoQ, vitamins, and antioxidant compounds.

When additional active agents are used in combination with the compoundsof the present invention, the additional active agents may generally beemployed in therapeutic amounts as indicated in the Physicians' DeskReference (PDR) 53rd Edition (1999), which is incorporated herein byreference, or such therapeutically useful amounts as would be known toone of ordinary skill in the art.

The compounds of the invention and the other therapeutically activeagents can be administered at the recommended maximum clinical dosage orat lower doses. Dosage levels of the active compounds in thecompositions of the invention may be varied so as to obtain a desiredtherapeutic response depending on the route of administration, severityof the disease and the response of the patient. When administered incombination with other therapeutic agents, the therapeutic agents can beformulated as separate compositions that are given at the same time ordifferent times, or the therapeutic agents can be given as a singlecomposition.

EXAMPLES

The invention will be further understood by the following non-limitingexamples.

Synthesis of Compounds Example 14-(Trifluoromethyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamideStep 1: 1-Bromo-2,5-dimethoxy-3,4,6-trimethylbenzene

To a solution of trimethylhydroquinone (30 g, 197 mmol.) in ethanol (200mL) was added dimethyl sulfate (33.6 mL, 405 mmol). The brown solutionwas degassed with hydrogen for 10 min and cooled in an ice-water bath.To the reaction mixture was added a 10% aqueous solution of sodiumhydroxide (42.6 mL, 414 mmol.), also degassed with hydrogen for 10 min.The reaction mixture was sealed and allowed to warm to room temperatureover 60 min. After 60 min, HPLC analysis indicated that the reaction wascomplete. Excess reagent was quenched with concentrated ammoniumhydroxide (150 mL) and the resulting black mixture was stirred for 30min. The reaction mixture was diluted in water (100 mL) and extractedwith methyl t-butyl ether (MTBE) (2×400 mL). The combined organics werewashed with brine (50 mL), dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo to give 32 g brown oil which wasused without further purification. ¹H NMR (CDCl₃, 400 MHz) 6.58 (s, 1H),3.81 (s, 3H), 3.70 (s, 3H), 2.35 (s, 3H), 2.25 (s, 3H), 2.18 (s, 3H)ppm. The brown residue was taken up in acetic acid (60 mL). To theresulting solution was added a solution of bromine (9.27 mL, 181 mmol)in acetic acid (150 mL), dropwise over 20 min. After an additional 20minutes, HPLC analysis indicated that the reaction was complete. Thereaction was then diluted with toluene (100 mL), concentrated, and theresidue taken up in i-propyl acetate (250 mL), and rinsed with 2.5 Mpotassium carbonate and brine (50 mL each), dried over anhydrous sodiumsulfate, filtered, and concentrated in vacuo to give a brownish oilwhich solidified on standing. Digestion in 150 mL of 4:1 water:ethanolmixture produced compound 1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzeneas an off-white solid, which was collected by filtration (26 g). ¹H NMR(CDCl₃, 400 MHz) 3.73 (s, 3H), 3.65 (s, 3H), 2.36 (s, 3H), 2.24 (s, 3H),2.18 (s, 3H) ppm.

Step 2: 2,5-Dimethoxy-3,4,6-trimethylbenzaldehyde

1-Bromo-2,5-dimethoxy-3,4,6-trimethylbenzene from Step 1 (5 g, 19.3mmol, 1 equiv.) was dissolved in benzene (2×20 mL) and the solventremoved in vacuo to remove residual water. The dry solid was dissolvedin toluene (100 mL) and the resulting solution cooled in an ice-waterbath. To the colorless solution was added n-BuLi (1.6 M in hexanes, 16mL, 26.9 mmol, 1.4 equiv.) dropwise over 1 min. After 2 min stirring,the resulting aryllithium species was quenched with DMF (7 mL, 90 mmol,4.5 equiv.). Following an additional 30 min, excess base was quenchedwith 1 M aqueous citric acid (20 mL), and the mixture diluted in ethylacetate (100 mL). The organics were removed, rinsed with brine (30 mL),dried over anhydrous sodium sulfate, filtered, and concentrated in vacuoto give 4.5 g 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde as an orangesolid, which was used without further purification. ¹H NMR (CDCl₃, 400MHz) 10.5 (s, 1H), 3.79 (s, 3H), 3.63 (s, 3H), 2.55 (s, 3H), 2.31 (s,3H), 2.23 (s, 3H) ppm.

Step 3: 1,4-Dimethoxy-2,3,5-trimethyl-6-(2-nitrovinyl)benzene

In a 500 mL round bottom flask was placed2,5-dimethoxy-3,4,6-trimethylbenzaldehyde (2.5 g, 12 mmol) and ammoniumacetate (1.3 g, 17 mmol). The solids were taken up in nitromethane (240mL), and the mixture warmed to 80° C. for 90 min. After the reaction wascomplete, volatiles were removed in vacuo, the residue was dissolved inethyl acetate (200 mL), washed with water and brine (50 mL each), driedover anhydrous sodium sulfate, filtered, and concentrated in vacuo togive 3.3 g 1,4-dimethoxy-2,3,5-trimethyl-6-(2-nitrovinyl)benzene as ayellow solid. Further purification was performed by digesting the solidproduct in cyclohexane for 3 hrs, after which the 2.5 g pure compound1,4-dimethoxy-2,3,5-trimethyl-6-(2-nitrovinyl)benzene was obtained. ¹HNMR (CDCl₃, 400 MHz) 8.24 (d, 1H), 7.95 (d, 1H), 3.65 (s, 3H), 3.63 (s,3H), 2.41 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H) ppm.

Step 4: 2-(2,5-Dimethoxy-3,4,6-trimethylphenyl)ethanamine

To a stirring suspension of lithium aluminum hydride (1.63 g, 42.8 mmol,6.0 equiv) in THF (15 mL) at 0° C. was added a solution of1,4-dimethoxy-2,3,5-trimethyl-6-(2-nitrovinyl)benzene (1.8 g, 7.14 mmol)in THF (15 mL) over 30 min. Following addition, the mixture was warmedto 60° C. and stirred for 2 hr. After this time, the reaction was deemedcomplete by HPLC analysis, the mixture was slowly transferred to 100 mL6M aqueous sodium hydroxide and stirred for 20 min. The resultingsuspension was filtered in vacuo and the cake rinsed with i-propylacetate (200 mL). The organics were removed and the remaining aqueouslayer was extracted 2× with i-propyl acetate (200 mL), combined, driedover anhydrous sodium sulfate, filtered, and concentrated in vacuo togive 1.6 g of light brown oil, which solidified on standing to givecrude amine 2-(2,5-dimethoxy-3,4,6-trimethylphenyl)ethanamine. ¹H NMR(CDCl₃, 400 MHz) 3.63 (s, 3H), 3.59 (s, 3H), 2.79 (m, 2H), 2.63 (m, 2H),2.20 (s, 3H), 2.15 (s, 3H) ppm.

Step 5:4-(Trifluoromethyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide

To a stirring solution of crude2-(2,5-dimethoxy-3,4,6-trimethylphenyl)ethanamine (300 mg, 1.34 mmol) in3 mL DMF at 23° C. was added 4-(trifluoromethyl)benzoyl chloride (300μL, 2.00 mmol) and pyridine (270 μL, 3.35 mmol). After 15 min, HPLCanalysis indicated that the reaction was complete. The mixture wasdiluted in water (15 mL) and ethyl acetate (25 mL). The organics wereremoved and washed again with brine (2×15 mL), dried over anhydroussodium sulfate, filtered, and concentrated in vacuo to give 550 mg ofcolorless solid intermediate amide. The intermediate compound wasdissolved in dioxane (6 mL) and water (2 mL) was added. To thisresulting solution was added ceric ammonium nitrate (1.6 g, 2.92 mmol,2.1 equiv.), after which a bright orange color developed. After 15minutes, the solution had become more yellow and HPLC analysis indicatedthat the reaction was complete. The reaction mixture was diluted inethyl acetate (8 mL) and brine (4 mL), the organics were removed, driedover anhydrous sodium sulfate, filtered, and concentrated in vacuo togive 500 mg of yellow/green solid. Purification was accomplished bysilica gel chromatography (gradient elution 10→30% ethylacetate/heptane), affording 290 mg of4-(trifluoromethyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;as a pale yellow solid. ¹H-NMR (400 MHz, CDCl₃, 25° C.) 7.88 (d, 2H),7.68 (d, 2H), 6.78 (s, 1H), 3.58 (m, 2H), 2.82 (t, 2H), 2.12 (s, 3H),2.01 (s, 6H) ppm.

Similarly following the procedure described for Example, the followingcompounds were prepared:

-   2-(4-fluorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)    acetamide; ¹H-NMR (400 MHz, CD₃OD) 7.18 (t, 2H), 7.01 (t, 2H), 5.53    (s, 1H), 3.48 (s, 2H), 3.33 (t, 2H), 2.62 (t, 2H), 1.99 (s, 3H),    1.97 (s, 6H) ppm;-   2-(4-chlorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)    acetamide; ¹H-NMR (400 MHz, CD₃OD) 7.32 (d, 2H), 7.18 (d, 2H), 5.65    (s, 1H), 3.48 (s, 2H), 3.33 (t, 2H), 2.64 (t, 2H), 2.01 (s, 3H),    1.98 (s, 6H) ppm;-   4-fluoro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;    ¹H-NMR (400 MHz, CD₃OD) 7.78 (m, 2H), 7.08 (t, 2H), 6.58 (s, 1H),    3.58 (m, 2H), 2.82 (t, 2H), 2.12 (s, 3H), 2.01 (s, 6H) ppm;-   4-chloro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;    ¹H-NMR (400 MHz, CD₃OD) 7.68 (d, 2H), 7.40 (d, 2H), 6.60 (s, 1H),    3.58 (m, 2H), 2.82 (t, 2H), 2.12 (s, 3H), 2.01 (s, 6H) ppm;-   N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;    ¹H-NMR (400 MHz, CDCl3) 7.78 (d, 2H), 7.50 (m, 1H), 7.42 (m, 2H),    6.58 (s, 1H), 3.58 (m, 2H), 2.82 (t, 2H), 2.12 (s, 3H), 2.01 (s, 6H)    ppm;-   3-(4-fluorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)propanamide;    ¹H-NMR (400 MHz, CDCl₃) 7.15 (t, 2H), 6.92 (t, 2H), 5.65 (bs, 1H),    3.28 (m, 2H), 2.85 (t, 2H), 2.62, (t, 2H), 2.40 (t, 2H), 2.02 (s,    3H), 1.98 (s, 6H) ppm;-   2-(2-methoxyphenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;    ¹H-NMR (400 MHz, CDCl₃) 8.20 (t, 1H), 8.02 (bs, 1H), 7.42 (t, 1H),    7.05 (t, 1H), 6.98 (d, 1H), 3.98 (s, 3H), 3.58 (m, 2H), 2.82 (t,    2H), 2.12 (s, 3H), 2.02 (s, 6H) ppm;-   2-(naphthalen-1-yl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;    ¹H-NMR (400 MHz, CDCl₃) 7.82 (m, 3H), 7.8 (m, 3H), 7.38 (d, 1H),    5.52 (bs, 1H), 3.98 (s, 2H), 3.22, (m, 2H), 2.55 (t, 2H), 1.98 (s,    3H), 1.94 (s, 6H) ppm;    -   2-(4-methoxyphenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;        ¹H-NMR (400 MHz, CDCl₃) 7.22 (s, 1H), 6.78 (m, 3H), 5.62 (bs,        1H), 3.78 (s, 3H), 3.42, (s, 2H), 3.32, (m, 2H), 2.60 (t, 2H),        2.02 (s, 3H), 1.97 (s, 6H) ppm;-   1-(4-methoxyphenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)cyclopropanecarboxamide;    ¹H-NMR (400 MHz, CDCl₃) 7.22 (d, 2H), 6.82 (d, 2H), 5.58 (bs, 1H),    3.72 (s, 3H), 3.22 (m, 2H), 2.60 (t, 2H), 2.02 (s, 3H), 1.98 (s,    6H), 1.56 (t, 2H), 0.98 (t, 2H) ppm;-   1-phenyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)cyclopropanecarboxamide;    ¹H-NMR (400 MHz, CDCl₃) 7.38 (s, 5H), 5.48 (bs, 1H), 3.22 (m, 2H),    2.60 (t, 2H), 2.02 (s, 3H), 1.98 (s, 6H), 1.56 (t, 3H), 1.02 (t, 2H)    ppm;-   4-cyano-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;    ¹H-NMR (400 MHz, CDCl₃) 7.88 (d, 2H), 7.78 (d, 2H), 6.78 (bs, 1H),    3.58 (m, 2H), 2.82 (t, 2H), 2.12 (s, 3H), 2.01 (s, 6H) ppm;-   4-methyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;    ¹H-NMR (400 MHz, CDCl₃) 7.88 (d, 2H), 7.78 (d, 2H), 6.78 (bs, 1H),    3.58 (m, 2H), 2.82 (t, 2H), 2.12 (s, 3H), 2.01 (s, 6H) ppm;-   4-acetyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;    ¹H-NMR (400 MHz, CDCl₃) 8.18 (d, 2H), 8.10 (d, 2H), 6.70 (bs, 1H),    3.58 (m, 2H), 2.85 (t, 2H), 2.55, (s, 3H), 2.12 (s, 3H), 2.01 (s,    6H) ppm;-   2-(4-methoxyphenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;    ¹H-NMR (400 MHz, CDCl₃) 7.15 (d, 2H), 6.82 (d, 2H), 5.58 (bs, 1H),    6.3.80 (s, 3H), 3.45 (s, 2H), 3.30 (m, 2H), 2.62 (t, 2H), 1.99 (s,    3H), 1.97 (s, 6H) ppm;-   2-(4-fluorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;    ¹H-NMR (400 MHz, CDCl₃) 7.18 (t, 2H), 7.01 (t, 2H), 5.53 (s, 1H),    3.48 (s, 2H), 3.33 (t, 2H), 2.62 (t, 2H), 1.99 (s, 3H), 1.97 (s, 6H)    ppm;-   2-(4-chlorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;    ¹H-NMR (400 MHz, CDCl₃) 7.32 (d, 2H), 7.18 (d, 2H), 5.65 (s, 1H),    3.48 (s, 2H), 3.33 (t, 2H), 2.64 (t, 2H), 2.01 (s, 3H), 1.98 (s, 6H)    ppm;-   2-(4-(trifluoromethyl)phenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;    ¹H-NMR (400 MHz, CDCl₃) 7.88 (d, 2H), 7.68 (d, 2H), 6.78 (s, 1H),    3.58 (m, 2H), 2.82 (t, 2H), 2.12 (s, 3H), 2.01 (s, 6H) ppm;-   4-fluoro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;    ¹H-NMR (400 MHz, CDCl₃) 7.78 (m, 2H), 7.08 (t, 2H), 6.58 (s, 1H),    3.58 (m, 2H), 2.82 (t, 2H), 2.12 (s, 3H), 2.01 (s, 6H) ppm;-   4-chloro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;    ¹H-NMR (400 MHz, CDCl₃) 7.68 (d, 2H), 7.40 (d, 2H), 6.60 (s, 1H),    3.58 (m, 2H), 2.82 (t, 2H), 2.12 (s, 3H), 2.01 (s, 6H) ppm;-   2-hydroxy-2-phenyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;    ¹H-NMR (400 MHz, CDCl₃) 7.37 (s, 5H), 6.32 (br s, 1H), 4.95 (s, 1H),    3.50 (s, 1H), 3.39 (q, 2H), 2.66 (t, 2H), 2.00 (s, 3H), 1.98 (s, 6H)    ppm;-   2-(4-chlorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)propanamide;    ¹H-NMR (400 MHz, CDCl₃) 7.27 (d, 2H), 7.19 (d, 2H), 5.60 (s, 1H),    3.41 (q, 1H), 3.30 (m, 2H), 2.60 (m, 2H), 2.01 (s, 6H), 1.98 (s,    6H), 1.44 (d, 3H) ppm;-   2-(4-fluorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)propanamide;    ¹H-NMR (400 MHz, CDCl₃) 7.20 (d, 2H), 6.99 (d, 2H), 5.60 (s, 1H),    3.42 (q, 1H), 3.30 (m, 2H), 2.61 (m, 2H), 2.00 (s, 6H), 1.97 9s,    3H), 1.44 (d, 3H) ppm;-   2-hydroxy-2-(4-(trifluoromethyl)phenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;    ¹H-NMR (400 MHz, CDCl₃) 7.62 (d, 2H), 7.54 (d, 2H), 6.44 (s, 1H),    5.08 (s, 1H), 3.52 (s, 1H), 3.38 (m, 2H), 2.68 (t, 2H), 2.01 (s,    6H), 1.97 (s, 3H) ppm;-   2-(4-chlorophenyl)-2-hydroxy-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;    ¹H-NMR (400 MHz, CDCl₃) 7.50 (s, 4H), 6.38 (s, 1H), 4.98 (s, 1H),    3.49 (s, 1H), 3.39 (q, 2H), 2.64 (t, 2H), 2.00 (s, 6H), 1.98 (s, 3H)    ppm;-   N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;    ¹H-NMR (400 MHz, CDCl₃) 7.78 (d, 2H), 7.50, (m, 1H), 7.42 (m, 2H),    6.58 (s, 1H), 3.58 (m, 2H), 2.82 (t, 2H), 2.12 (s, 3H), 2.01 (s, 6H)    ppm;-   N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)methane    sulfonamide; ¹H-NMR (400 MHz, CDCl₃) 4.40 (br s, 1H), 3.24 (q, 2H),    2.96 (s, 3H), 2.79 (t, 2H), 2.08 (s, 1H), 2.03 (s, 3H), 2.02 (s, 3H)    ppm;-   4-fluoro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzene    sulfonamide; ¹H-NMR (400 MHz, CDCl₃) 7.81 (d, 2H), 7.09 (d, 2H),    4.63 (br t, 1H), 3.08 (q, 2H), 2.63 (t, 2H), 2.02 (s, 6H), 1.99 (s,    3H) ppm;-   N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;    ¹H-NMR (400 MHz, CDCl₃) 5.75 (br s, 1H), 3.36 (q, 2H), 2.70 (t, 2H),    2.11 (s, 3H), 2.02 (s, 3H), 1.95 (s, 3H) ppm;-   4-methoxy-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzenesulfonamide;    ¹H-NMR (400 MHz, CDCl₃) 7.70 (d, 2H), 6.98 (d, 2H), 4.58 (t, 1H),    4.85 (s, 3H), 3.11 (q, 2H), 2.64 (t, 2H), 1.98 (s, 6H), 1.96 (s, 3H)    ppm; and-   N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)nicotinamide    as the hydrochloride salt; ¹H-NMR (400 MHz, CD₃OD) 9.14 (d, 1H),    8.94 (dd, 1H), 8.79 (dt, 1H), 8.09 (dd, 1H), 3.56 (td, 2H), 2.86 (t,    2H), 2.05 (s, 3H), 1.99 (s, 6H) ppm.

Example 21-(4-Fluorobenzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea

To a stirring solution of 2-(2,5-dimethoxy-3,4,6-trimethylphenyl)ethanamine (150 mg, 670 μmol), prepared as in Example 1 Step 4, indioxane (3 mL) at 23° C. was added 4-fluorobenzylisocyanate (87 μL, 680μmol) in one portion. After addition, the colorless solution becamethick and viscous and a brown color developed. HPLC analysis after 15min indicated that the reaction was complete. At this point, excessreagent was quenched with 2.5 M aqueous potassium carbonate (5 mL), andthe reaction was diluted with ethyl acetate (10 mL). The organics wereremoved, washed with brine (5 mL), dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo to give 180 mg yellow solid. Theresulting urea (150 mg, 500 μmol) was used without further purification.The material was taken up in 2.5 mL dioxane with 1 mL water, and to theresulting solution was added ceric ammonium nitrate (550 mg, 1.1 mmol,2.1 equiv.). The yellow solution was stirred for 30 min, after whichHPLC analysis indicated that the reaction was complete. At this point,the mixture was diluted in ethyl acetate (10 mL), and washedsuccessively with water and brine (5 mL each). Organics were dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo to give110 mg of1-(4-fluorobenzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)ureaas a yellow solid. Purification by recrystallization from ethylacetate/heptane afforded 70 mg of bright yellow crystals. ¹H-NMR (400MHz, CDCl₃) 7.21 (t, 2H), 7.00 (t, 2H), 4.20 (s, 1H), 3.28 (t, 2H), 2.68(t, 2H), 1.99 (s, 3H), 1.97 (s, 6H) ppm.

Similarly following the procedure from Example 2, but substituting4-fluorobenzylisocyanate for the appropriate isocyanate, the followingcompounds were prepared:

-   1-(4-chlorobenzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;    ¹H-NMR (400 MHz, CD₃OD) 7.21 (m, 4H), 4.22 (d, 2H), 3.30 (t, 2H),    2.68 (t, 2H), 2.01 (s, 3H), 1.98 (s, 6H) ppm;-   1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;    ¹H-NMR (400 MHz, CD₃OD) 4.02 (t, 2H), 2.72 (t, 2H), 2.01 (s, 3H),    1.98 (s, 6H) ppm;-   1-ethyl-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;    ¹H-NMR (400 MHz, CDCl₃) 3.22 (m, 4H), 2.72 (t, 2H), 2.08 (s, 3H),    2.02 (s, 6H), 1.16 (t, 3H) ppm; and-   1-(4-(trifluoromethyl)benzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;    ¹H-NMR (400 MHz, CDCl₃) 7.40 (d, 2H), 7.29 (d, 2H), 4.95 (br s, 1H),    4.80 (s, 2H), 3.38 (q, 2H), 2.79 (t, 2H), 2.08 (s, 3H), 2.00 (s, 6H)    ppm.; and-   1-(pyridin-3-ylmethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea    ¹H-NMR (400 MHz, CDCl₃, 25° C.): δ=8.58 (s, 1H), 8.50 (d, 1H), 7.64    (d, 1H), 7.24 (dd, 1H), 5.02 (bs, 1H), 4.70 (t, 1H), 4.40 (d, 2H),    3.28, (dd, 2H), 2.66 (t 2H), 2.04 (s, 3H), 2.02 (s, 3H), 1.98 (s,    3H).

Similarly following the procedure from Example 2, but substituting4-fluorobenzylisocyanate for the appropriate chloroformate, thefollowing compound was prepared:

-   ethyl    2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethylcarbamate;    ¹H-NMR (400 MHz, CD₃OD) 4.00 (m, 2H), 3.20 (t, 2H), 2.70 (t, 2H),    2.01 (s, 3H), 1.99 (s, 6H), 1.18 (t, 3H) ppm.

Example 34-Oxo-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide

In a 20-mL scintillation vial,2-(2,5-dimethoxy-3,4,6-trimethylphenyl)ethanamine (300 mg, 1.34 mmol)and carbonyldiimidazole (260 mg, 1.61 mmol) were dissolved in 6 mLdioxane. The solution was stirred at ambient temperature for 15 min,when HPLC analysis indicated that an activated intermediate had formed.To the solution was added 4-piperidinone (270 mg, 1.74 mmol) and theresulting mixture was warmed to 80° C. After stirring for 1 hr, HPLCanalysis indicated that the reaction was complete. The mixture asdiluted with ethyl acetate (12 mL), washed successively with water andbrine (5 mL each), dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to give 470 mg orange oil which was oxidizedwithout further purification. The oily urea intermediate was dissolvedin acetonitrile (6 mL) and the resulting solution was diluted with water(3 mL). To the solution was added ceric ammonium nitrate (1.55 g, 2.8mmol). After 25 min, the orange color of the solution turned to brightyellow, and HPLC analysis indicated that the reaction was complete. Themixture was diluted in ethyl acetate (12 mL), washed successively withwater and brine (5 mL each), dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo to give 400 mg yellow oil.Purification was accomplished by silica gel chromatography (gradientelution 1:1 ethyl acetate:heptane→ethyl acetate) produced4-oxo-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide(190 mg) as yellow crystals. ¹H-NMR (400 MHz, CD₃OD) 6.72 (s, 1H), 3.32(t, 2H), 2.78 (t, 2H), 2.40 (t, 4H), 1.99 (s, 3H), 1.97 (s, 6H) ppm.

Similarly following the procedure from Example 3, but substituting4-piperidinone for the appropriate amine, the following compounds wereprepared:

-   4-acetyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;    ¹H-NMR (400 MHz, CD₃OD) 3.52 (m, 4H), 2.39 (t, 2H), 2.70 (t, 4H),    2.12 (s, 3H), 1.99 (s, 3H), 1.97 (s, 6H) ppm;-   4-hydroxy-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;    ¹H-NMR (400 MHz, CD₃OD) 3.75 (m, 2H), 3.25 (t, 2H), 2.95 (m. 2H),    2.70 (t, 2H), 1.99 (s, 3H), 1.97 (s, 6H), 1.78 (m, 2H), 1.38 (m, 2H)    ppm;-   N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;    ¹H-NMR (400 MHz, CD₃OD) 3.60 (2, 2H), 2.32 (t, 2H), 2.68 (t, 2H),    2.20 (d, 2H), 1.99 (s, 3H), 1.97 (s, 6H), 1.60 (m, 2H), 1.48 (m, 4H)    ppm;-   4-methyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;    ¹H-NMR (400 MHz, CD₃OD) 3.25 (t, 2H), 2.68 (t, 2H), 2.38 (t, 4H)    2.28 (s, 3H), 1.99 (s, 3H), 1.97 (s, 6H) ppm;-   4-benzyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;    ¹H-NMR (400 MHz, CD₃OD) 7.30 (m, 5H), 3.52 (s, 1H), 3.32 (t, 4H),    3.22 (t, 2H), 2.68 (t, 2H), 2.40 (t, 4H), 1.99 (s, 3H), 1.97 (s, 6H)    ppm;-   1,1-diethyl-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;    ¹H-NMR (400 MHz, CD₃OD) 3.32 (t, 2H), 3.20 (t, 4H), 2.70 (t, 2H),    1.99 (s, 3H), 1.97 (s, 6H), 1.03 (t, 6H) ppm;-   1-(2-hydroxyethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;    ¹H-NMR (400 MHz, CD₃OD) 3.52 (t, 2H), 3.25 (t, 2H), 3.18 (t, 2H)    3.68 (t, 2H), 2.01 (s, 3H), 1.98 (s, 6H) ppm;-   1-(2-(dimethylamino)ethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea,    isolated as the hydrochloride salt; ¹H-NMR (400 MHz, CD₃OD) 2.41 (t,    2H), 2.22 (t, 2H), 2.18 (t, 2H), 2.90 (s, 6H), 1.68 (t, 2H), 2.05    (s, 3H), 2.00 (s, 6H) ppm;-   1-(2-morpholinoethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;    ¹H-NMR (400 MHz, CD₃OD) 3.68 (d, 4H), 3.20 (m, 4H), 2.68 (t, 2H),    2.42 (s, 4H), 2.40 (t, 2H), 1.99 (s, 3H), 1.97 (s, 6H) ppm;-   4-fluoro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;    ¹H-NMR (400 MHz, CDCl₃) 4.89 (m, 1H), 3.45-3.26 (m, 6H), 2.73 (t,    2H), 2.06 (s, 3H), 2.00 (s, 6H) 1.80 (m, 4H) ppm; and-   4,4-difluoro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;    ¹H-NMR (400 MHz, CDCl₃) 5.00 (s, 1H), 3.44 (m, 4H), 3.33 (t, 2H),    2.72 (t, 2H), 2.09 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.95 (m, 4H)    ppm.

Example 43-Ethyl-1-methyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)ureaStep 1: 2-(2,5-Bis(benzyloxy)-3,4,6-trimethylphenyl)ethanamine

2,5-Bis(benzyloxy)-3,4,6-trimethylbenzaldehyde (3.2 g, 8.8 mmol) andammonium acetate (815 mg, 10.6 mmol) were taken up in nitromethane (44mL). The resulting solution was stirred at 80° C. for 1 hr, after whichHPLC analysis indicated that the reaction was complete. The reaction wasdiluted in 100 mL ethyl acetate and washed twice with brine (30 mL). Theorganics were dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to give 3.2 g yellow solid nitrostyrene, which wasused without further purification. The solid intermediate was dissolvedin 22 mL anhydrous THF and added dropwise to a slurry of lithiumaluminum hydride (2.1 g, 50 mmol, 6 equiv.) stirring at 0° C. After 60minutes, the addition was complete, and the mixture was warmed toreflux. The reaction stirred for an additional 18 hr, after which HPLCanalysis indicated that the reaction was not complete. At this time, themixture was cooled to ambient temperature and a second portion oflithium aluminum hydride (700 mg) was added. Following 30 min at reflux,the reaction was deemed complete. The mixture was slowly poured into 200mL 2.5 M sodium hydroxide stirring on ice-water bath. The resultingslurry was stirred for 20 minutes, diluted with isopropyl acetate (200mL), and filtered. The organics were removed and the aqueous layerwashed twice with 100 mL isopropyl acetate. The combined organics weredried over anhydrous sodium sulfate, filtered, and concentrated in vacuoto give 3.3 g 2-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)ethanamine asa white solid. ¹H-NMR (400 MHz, CD₃OD) 7.51-7.31 (m, 10H), 4.77 (s, 2H),4.72 (s, 2H), 2.83 (m, 2H), 2.71 (m, 2H), 2.24 (s, 3H), 2.22 (s, 3H),2.13 (s, 3H) ppm.

Step 2: 2-(2,5-Bis(benzyloxy)-3,4,6-trimethylphenyl)-N-methylethanamine

To a solution of 2-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)ethanamine(1.0 g, 2.65 mmol) in dioxane (6.6 mL) was addeddi-tert-butyldicarbonate (730 μL, 3.19 mmol), followed by aqueous sodiumhydroxide (2.5 M solution, 1.28 mL, 3.19 mmol). The reaction mixture wasstirred for 100 min, At this time, HPLC analysis indicated completeconversion to product. The mixture was then diluted in ethyl acetate (25mL), transferred to a separatory funnel, and washed with 1 M aqueoussodium bicarbonate (2×10 mL), saturated ammonium chloride (10 mL), andbrine (10 mL). The organic layer was dried over anhydrous sodiumsulfate, filtered, and concentrated in vacuo. The carbamate product wasthen dissolved in THF (13 mL), and the solution was treated with lithiumaluminum hydride (800 mg). The resulting slurry was warmed to reflux andstirred for 90 min, after which HPLC analysis indicated consumption ofstarting material. The mixture was subsequently added slowly to 75 mL2.5 M aqueous sodium hydroxide stirred over ice. The resulting greysuspension was stirred for 10 min, during which time the solids becamewhite. To the suspension was added 100 mL isopropyl acetate, and theresulting mixture was filtered, and transferred to a separatory funnel.The organics were removed and the aqueous layer washed with 50 mLisopropyl acetate. The combined organics were dried over anhydroussodium sulfate, filtered, and concentrated in vacuo to give 900 mg of2-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)-N-methylethanamine. ¹H-NMR(400 MHz, CD₃OD) 7.51-7.30 (m, 10H), 4.72 (s, 3H), 2.84 (s, 2H), 2.42(m, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H) ppm.

Step 3:3-Ethyl-1-methyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea

To a solution of2-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)-N-methylethanamine (100 mg,256 μmol, 1.0 equiv.) in dioxane (2 mL) was added ethylisocyanate (24μL, 307 μmol, 1.2 equiv.). After stirring for 30 min, HPLC analysisindicated that the reaction was complete. The mixture was diluted inethyl acetate (10 mL), washed with 1 M aqueous sodium bicarbonate andbrine (5 mL each), dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to give 174 mg yellow oil. The crude material wasdissolved in 2 mL TFA, charged with palladium on carbon (5%, 12 μmol,0.05 equiv.). The resulting suspension was bubbled with hydrogen gas for2 min, then warmed to 45° C. and stirred under an atmosphere of hydrogenfor 45 min. After this time, HPLC analysis indicated that the reactionwas complete. The mixture was filtered, and concentrated in vacuo togive a colorless solid. The crude material was dissolved in acetonitrile(2 mL) and water (0.5 mL), and the resulting solution was charged withceric ammonium nitrate (290 mg, 525 μmol, 2.1 equiv.). After stirringfor 10 min, HPLC analysis indicated that the reaction was complete. Thereaction mixture was partitioned between 10 mL ethyl acetate and 5 mLbrine. The organics were dried over anhydrous sodium sulfate, filtered,and concentrated in vacuo. Purification by silica gel chromatography(gradient elution: 40% ethyl acetate/heptane→80% ethyl acetate/heptane)afforded 2-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)-N-methylethanamineas a brownish solid (40 mg). ¹H-NMR (400 MHz, CDCl₃) 5.00 (br s, 1H),3.51 (br s, 2H), 3.30 (br s, 3H), 3.00 (br s, 2H), 2.74 (br s, 2H), 2.09(s, 3H), 2.01 (s, 6H), 1.85 (t, 3H) ppm.

2-(2,5-Bis(benzyloxy)-3,4,6-trimethylphenyl)-N-methylethanamine wasfunctionalized in a fashion analogous to the procedures described aboveto produce the compounds:

-   1-methyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;    ¹H-NMR (400 MHz, CD₃OD) 3.42 (t, 2H), 2.98 (s, 3H), 2.78 (t, 2H),    2.01 (s, 3H), 1.98 (s, 6H) ppm;-   3-(2-(dimethylamino)ethyl)-1-methyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;    ¹H-NMR (400 MHz, CD₃OD) 3.44 (t, 2H), 3.38 (t, 2H), 3.29 (s, 3H),    3.22 (s, 2H), 2.92 (s, 3H), 2.91 (s, 3H), 2.75 (t, 2H), 2.01 (s,    3H), 2.00 (s, 6H) ppm;-   3-(4-chlorobenzyl)-1-methyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;    ¹H-NMR (400 MHz, CDCl₃) 5.41 (br s, 1H), 4.41 (d, 2H), 3.22 (t, 2H),    2.95 (s, 3H), 2.70 (t, 2H), 2.08 (s, 3H), 2.01 (s, 3H), 1.98 (s, 3H)    ppm;-   N-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-4-fluorobenzenesulfonamide;    ¹H-NMR (400 MHz, CDCl₃) 7.85 (q, 2H), 7.42 (d, 2H), 7.17 (t, 2H),    7.06 (d, 2H), 4.59 (t, 1H), 3.15 (q, 2H), 2.72 (t, 2H), 2.12 (s,    3H), 1.95 (s, 3H) ppm;-   N-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-4,4-difluorocyclohexanecarboxamide;    ¹H-NMR (400 MHz, CDCl₃) 7.46 (d, 2H), 7.06 (d, 2H), 4.88, (t, 1H),    3.41 (m, 4H), 3.53 (q, 2H), 2.76 (t, 2H), 2.17 (s, 3H), 1.99 (s,    3H), 1.84 (m, 4H) ppm;-   1-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-3-ethylurea;    ¹H-NMR (400 MHz, CDCl₃) 7.42 (d, 2H), 7.09 (d, 2H), 4.43 (br s, 1H),    3.30 (q, 2H), 3.16 (q, 2H), 2.75 (t, 2H), 2.18 (s, 3H), 1.93 (s,    3H), 1.10 (t, 3H) ppm; and-   1-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea,    ¹H-NMR (400 MHz, CD₃OD) 7.42 (d, 2H), 7.18 (d, 2H), 3.26 (t, 2H),    2.72 (t, 2H), 2.12 (s, 3H), 1.89 (s, 3H) ppm.

Example 5N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-4-methylbenzenesulfonamideStep 1: 6-(Methoxymethoxy)-2,2,7,8-tetramethylchroman-5-carbaldehyde

2,2,7,8-Tetramethylchroman-6-ol (2.0 g, 9.7 mmol) and hexamethylenetetramine (680 mg, 4.05 mmol) were weighed into a 20-mL scintillationvial, after which TFA (640 μL) and acetic acid (6.4 mL) were added. Thevial was sealed, and the resulting mixture heated to 100° C. for 90 min,during which time a deep red color developed. The mixture was thenconcentrated to a red oil at 55° C. in vacuo. The darkly-colored residuewas stirred in a biphasic mixture of 50 mL ethylacetate (EtOAc) and 50mL 1 M aqueous sodium bicarbonate for 1 hr. At this time, the organiclayer was removed, and successively washed with 1 M aqueous sodiumbicarbonate (2×50 mL), 1 M aqueous citric acid (2×50 mL), and brine (50mL). The residual organics were dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo to 2.1 g yellow oil. Crudepurification was accomplished by silica gel chromatography (gradientelution 0→10% EtOAc/Heptane) to obtain 1.0 g6-hydroxy-2,2,7,8-tetramethylchroman-5-carbaldehyde product, which wasimmediately dissolved in DMF (88 mL) and treated with MOMCI (670 μL, 8.8mmol) and Di-isopropyl ethyl amine (DiPEA) (2.2 mL, 13.2 mmol). Thereaction mixture was heated to 50° C. for 2 hr and then subsequentlydiluted in EtOAc (75 mL). The organics were washed successively with 1 Maqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (25 mLeach), dried over anhydrous sodium sulfate, filtered, and concentratedin vacuo. Silica gel chromatography (gradient elution 0→15%EtOAc/Heptane) afforded the6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-carbaldehyde (920 mg) asa colorless oil. ¹H NMR (CDCl₃, 400 MHz) 10.4 (s, 1H), 4.93 (s, 2H),3.56 (s, 3H), 3.06 (t, 2H), 2.18 (s, 3H), 2.13 (s, 3H), 1.72 (t, 2H),1.28 (s, 6H) ppm.

Step 2: 2-(6-(Methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethanamine

6-(Methoxymethoxy)-2,2,7,8-tetramethylchroman-5-carbaldehyde (500 mg,1.7 mmol) and ammonium acetate (157 mg, 1.7 mmol) were taken up innitromethane (11.6 mL) and the mixture was warmed to 80° C. for 1.5 hrs.After this time, the reaction was judged to be complete and the mixturewas diluted in EtOAc (75 mL), washed once with brine, dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo. Silicagel chromatography (gradient elution 0→15% EtOAc/Heptane) afforded theyellow solid nitrostyrene intermediate (500 mg). ¹H NMR (CDCl₃, 400 MHz)8.30 (d, 2H), 7.80 (d, 2H), 4.82 (s, 2H), 3.76 (s, 3H), 2.78 (t, 2H),2.20 (s, 3H), 2.12 (s, 3H), 1.80 (t, 2H), 1.26 (s, 6H) ppm. Theintermediate compound was dissolved in 5 mL THF and added dropwise over30 min to a stirring suspension of LiAlH₄ (400 mg, 10 mmol) in 3 mL THFat 0° C. After addition was complete, the mixture was stirred at 50° C.After 5 hr total, excess reagent was quenched by addition of 3 g sodiumsulfate dodecylhydrate. The resulting suspension was stirred for 30 min,during which time the grey color turned to white. Subsequently, thesuspension was filtered, and the filtrate concentrated in vacuo toprovide 2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethanamineas a colorless oil, 450 mg. ¹H NMR (CD₃OD, 400 MHz) 4.84 (s, 2H), 3.60(s, 3H), 2.80 (m, 4H), 2.70 (t, 2H), 2.14 (s, 3H), 2.06 (s, 3H), 1.78(t, 2H), 1.22 (s, 3H), 1.20 (s, 3H) ppm.

Step 3:N-(2-(6-(Methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethyl)-4-methylbenzenesulfonamide

To a solution of2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethanamine (450mg, 1.8 mmol) in THF (4.2 mL) at 23° C. was added tosyl chloride (390mg, 2.0 mmol) and pyridine (270 μL, 3.4 mmol). The reaction mixture wasstirred at room temperature for 45 min, diluted in 50 mL EtOAc, washedwith 1 M aqueous citric acid (2×25 mL) and brine (1×25 mL). The remainedorganics were dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography (gradient elution 5→35% EtOAc/Heptane) to produce 300 mgN-(2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethyl)-4-methylbenzenesulfonamide.¹H NMR (CDCl₃, 400 MHz) 7.48 (d, 2H), 7.09 (m, 8H), 5.20 (s, 1H), 4.82(s, 2H), 3.55 (s, 3H), 3.10 (q, 2H), 2.70 (t, 2H), 2.45 (t, 2H) 2.35 (s,3H), 2.11 (s, 3H), 2.04 (s, 3H), 1.65 (t, 2H), 1.20 (s, 6H) ppm.

Step 4:N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-4-methylbenzenesulfonamide

A solution ofN-(2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethyl)-4-methylbenzenesulfonamide(300 mg, 670 μmol) in methanol (2 mL) at 23° C. was charged withconcentrate HCl (approx. 20 μL). The resulting mixture was stirred at40° C. for 45 min, after which the reaction was deemed complete by TLCanalysis. The mixture was diluted in EtOAc (25 mL), washed once with 1 Maqueous sodium bicarbonate, dried over anhydrous sodium sulfate, andconcentrated in vacuo to afford the desired phenol. ¹H NMR (CDCl₃, 400MHz) 7.59 (d, 2H), 7.17 (d, 2H), 5.0 (br s, 1H), 3.13 (t, 2H), 2.80 (t,2H), 2.51 (t, 2H), 2.38 (s, 3H), 2.12 (s, 3H), 2.09 (s, 3H), 1.69 (t,2H), 1.24 (s, 6H) ppm. The crude phenol was then dissolved in 2 mL MeCNand the solution cooled to 0° C. in an ice bath. To this solution wasadded in a dropwise fashion an aqueous solution of CAN (700 mg, 1.4mmol, 1.5 mL). A yellow color emerged immediately upon addition, and thetitration was complete when a small amount of reddish materialpersisted. At this point, the mixture was partitioned between EtOAc andbrine, the organic layer removed, dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo. The residue was purified by silicagel chromatography (gradient elution 20→50% EtOAc/Heptane) to produce150 mgN-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-4-methylbenzenesulfonamide,as a yellow foam. ¹H NMR (CDCl₃, 400 MHz) 7.67 (d, 2H), 7.25 (d, 2H),5.10 (s, 1H), 3.10 (t, 2H), 2.69 (t, 2H), 2.48 (s, 2H), 2.39 (s, 3H),2.00 (s, 3H), 1.96 (s, 3H), 1.58 (t, 2H), 1.28 (s, 6H) ppm.

Example 6N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)methanesulfonamide

A suspension of the hydrochloride salt of2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethanamine (100mg, 300 μmol), prepared as described in Example 1, in 1.5 mL MeCN wascharged with pyridine (300 μL) followed by methanesulfonyl chloride (30μL, 360 μmol). The suspension was stirred at 23° C. for 90 min, thendiluted in isopropyl acetate (30 mL) and washed successively with 2.5 Maqueous sodium hydroxide, 1 M aqueous citric acid, and brine (1×15 mLeach). The remaining organics were dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo to a yellowish oil. The oily residuewas dissolved in methanol (3 mL), treated with concentrated HCl (approx.30 μL), and the resulting mixture was warmed to 40° C. After 1 hr, thereaction was judged to be complete by TLC analysis, and was diluted into50 mL EtOAc. The mixture was washed with 1 M aqueous sodium bicarbonateand brine (1×20 mL each), dried over anhydrous sodium sulfate, filtered,and concentrated in vacuo. Purification by silica gel chromatography(gradient elution 20→60% EtOAc/Heptane) produced yellow solid chromanmesylate intermediate (48 mg). ¹H NMR (CDCl₃, 400 MHz) 3.31 (m, 2H),2.90 (t, 2H), 2.78 (s, 2H), 2.67 (t, 2H), 2.14 (s, 3H), 2.09 (s, 3H),1.76 (t, 2H), 1.22 (s, 6H) ppm. The resulting chroman was oxidized withCAN in a manner analogous to that used in Step 4 of Example 1. Silicagel purification (gradient elution 30→80% EtOAc/Heptane) affordedN-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)methanesulfonamideas a yellow oil (25 mg). ¹H NMR (CDCl₃, 400 MHz) 4.82 (t, 2H), 3.26 (q,2H), 2.92 (s, 3H), 2.78 (t, 2H), 2.61 (m, 2H), 1.99 (s, 6H), 1.59 (m,2H), 1.26 (s, 6H) ppm.

Example 7N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-benzamide

N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamidewas prepared from2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethanamine usingbenzoyl chloride in an analogous procedure to that described in Example2. The final compound was purified as a yellow solid using silica gelchromatography (gradient elution 10→40% EtOAc/Heptane). ¹H NMR (CDCl₃,400 MHz) 7.41 (m, 2H), 7.47 (m, 1H), 7.39 (m, 2H), 6.59 (m, 1H), 3.54(q, 2H), 2.89 (t, 2H), 2.70 (m, 2H), 2.00 (s, 6H), 1.63 (m, 2H), 1.27(s, 6H) ppm.

Example 85-(1,2-Dithiolan-3-yl)-N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)pentanamide

Racemic lipoic acid (100 mg, 500 μmol) and CDI (87 mg, 540 μmol) wastaken up and stirred in THF (1.1 mL) at 23° C. After 45 min, the yellowsolution was added dropwise to a suspension of the hydrochloride salt of2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethanamine (150mg, 450 μmol), in THF (1.1 mL) containing DiPEA (90 μL, 540 μmol). Afterstirring for an additional 3.5 hrs, the mixture was diluted in EtOAc (40mL), washed with 1 M aqueous sodium bicarbonate, 1 M aqueous citricacid, and brine (1×20 mL each). The remaining organics were dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo. Theunpurified residue was dissolved in 2 mL methanol at 40° C. ConcentratedHCl (approx. 30 μL) was added to the solution and stirring continued for1 hr. At the completion of the reaction, the mixture was diluted inEtOAc (40 mL), washed with 1 M aqueous sodium bicarbonate, 1 M aqueouscitric acid, and brine (1×20 mL each). The remaining organics were driedover anhydrous sodium sulfate, filtered, and concentrated in vacuo.Purification by silica gel chromatography (gradient elution 30→70%EtOAc/Heptane) afforded the desired chroman amide as a colorless oil,140 mg. ¹H NMR (CDCl₃, 400 MHz) 6.05 (m, 1H), 3.55 (m, 1H), 3.30 (q,2H), 3.20-3.05 (m, 2H), 2.81 (t, 2H), 2.63 (t, 2H), 2.42 (m, 1H), 2.20(m, 1H), 2.17 (s, 3H), 2.09 (s, 3H), 1.90 (m, 1H), 1.75 (t, 2H),1.70-1.40 (m, 6H), 1.25 (s, 6H) ppm. CAN-mediated oxidation of theintermediate amide using the procedure described above produced5-(1,2-dithiolan-3-yl)-N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)pentanamideas a yellow oil that was purified by silica gel chromatography (gradientelution 30→70% EtOAc/Heptane). ¹H NMR (CDCl₃, 400 MHz) 5.88 (m, 1H),3.54 (m, 1H), 3.30 (m, 2H), 3.16-3.08 (m, 2H), 2.67 (m, 4H), 2.43 (m,1H), 2.14 (t, 2H), 1.95 (s, 6H), 1.88 (m, 1H), 1.73-1.58 (m, 4H), 1.44(m, 3H), 1.26 (s, 6H) ppm.

Example 91-Ethyl-3-(2(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea

A suspension of the hydrochloride salt of2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethanamine (75 mg,225 μmol) in THF (2.25 mL) was charged with DiPEA (46 μL, 270 μmol),followed by ethylisocyanate (20 μL, 250 μmol). The reaction mixture wasstirred for 20 min at 23° C., and was subsequently concentrated invacuo. The solid residue was taken up in methanol (2 mL), warmed to 40°C., and treated with approx. 30 μL conc. HCl. After 1 hr, TLC analysisindicated that the reaction was complete. The mixture was diluted inEtOAc (40 mL), washed with 1 M aqueous sodium bicarbonate, 1 M aqueouscitric acid, and brine (1×20 mL each). The remaining organics were driedover anhydrous sodium sulfate, filtered, and concentrated in vacuo.Purification by silica gel chromatography (gradient elution 50→85%EtOAc/Heptane) afforded the desired chroman as a white solid, 40 mg.CAN-mediated oxidation as described above afforded the desired1-ethyl-3-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)ureaas a yellow semi-solid. Purification was accomplished using silica gelchromatography (gradient elution 60→90% EtOAc/Heptane). ¹H NMR (CDCl₃,400 MHz) 3.32 (m, 2H), 3.24 (m, 2H), 2.73 (t, 2H), 2.65 (m, 2H), 1.99(s, 6H), 1.61 (m, 2H), 1.24 (s, 6H), 1.14 (t, 3H) ppm.

Example 10N-(2-(2-(3-Hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)hexanamide

N-(2-(2-(3-Hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)hexanamidewas prepared with hexanoic anhydride using an analogous procedure tothat described in Example 5. The final compound was purified as a yellowoil using silica gel chromatography (gradient elution 20→60%EtOAc/Heptane). ¹H NMR (CDCl₃, 400 MHz) 5.82 (m, 1H), 3.32 (m, 2H),2.71-2.64 (m, 4H), 2.12 (t, 2H), 1.99 (s, 6H), 1.62-1.54 (m, 4H),1.30-1.23 (m, 10H), 0.86 (t, 3H) ppm.

Example 112-(4-(4-hydroxypiperidin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dioneStep 1: 1,4-Dimethoxy-2,3,5-trimethylbenzene

2,3,5-Trimethylhydroquinone (50.2 g) in 400 mL EtOH was treated with asolution of 10 g Na₂S₂O₃.5H₂O in 50 mL H₂O followed by Me₂SO₄ (68 mL,2.2 equiv.). To this was added slowly 10 M NaOH (100 mL, 3.0 equiv.) viadropping funnel until the reaction temperature reached 60° C. (65 mLadded). The remaining 35 mL NaOH solution was added slowly, dropwiseover 1 h to maintain a minimum 40° C. reaction temperature. After 2.0 h,the reaction vessel had returned to ambient temperature and anadditional portion of Me₂SO₄ (10 mL, 13.3 g) was added causing a slightrise in temperature. After 1 h, the reaction had returned to roomtemperature, 100 mL conc. NH₄OH was added and let stir overnight. Thered-brown solution was diluted with isopropyl acetate, the organicswashed with 200 mL H₂O, 200 mL 1.0 M NaHCO₃ and 2×200 mL saturatedaqueous NaCl, dried over MgSO₄ and concentrated to give 61.2 g of1,4-dimethoxy-2,3,5-trimethylbenzene as a brown oil. ¹H NMR (400 MHz,CDCl₃) δ=6.53 (s, 1H), 3.78 (s, 3H), 3.66 (S, 3H), 2.28 (s, 3H), 2.20(s, 3H), 2.12 (s, 3H) ppm.

Step 2: 1-Bromo-2,5-dimethoxy-3,4,6-trimethylbenzene

A stirred solution of 1,4-dimethoxy-2,3,5-trimethylbenzene (61.2 g) wasdissolved into 350 mL acetic acid (1.0 M) and treated with a solution ofBr₂ (17.7 mL, 55.1 g) in 115 mL acetic acid over 1 h. The reaction wasstirred for an additional hour and poured over 1.5 l ice. The cloudysolution was filtered and the solids washed 2×200 mL H₂O and dried underhigh vacuum. The product was azeotroped twice from toluene to removeresidual acetic acid to give 73.6 g of1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene as a red-brown solid; Mp57.2-62.8° C.; ¹H NMR (400 MHz, CDCl₃) δ=3.75 (s, 3H), 3.66 (s, 3H),2.35 (s, 3H), 2.22 (s, 3H), 2.17 (s, 3H) ppm.

Step 3: 2,5-Dimethoxy-3,4,6-trimethylbenzaldehyde

1-Bromo-2,5-dimethoxy-3,4,6-trimethylbenzene (15 g) in 200 mL toluenewas cooled to 0° C. and treated with 33 mL 2.5 M n-BuLi (in hexanes, 1.4equiv.) over 10 minutes. Precipitates formed almost immediately uponn-BuLi addition. The suspension was stirred for 5 minutes and treatedwith dimethylformamide (DMF) (20 mL, 289 mmol). After 15 minutes at roomtemperature, citric acid solution was added (1 M, 200 mL) followed by100 mL ethyl acetate and the emulsion separated. The organic layer waswashed 3×50 mL 2.5 M HCl, 2×50 mL saturated aqueous NaCl, filtered,dried over Na₂SO₄ and concentrated to a brown, crystalline solid. Thecrude solid was taken up into 40 mL heptane and stirred overnight as anoff-white solid suspended in a brown colored solution. The color of thesolid lightened as stirring continued. The off-white solid was thenfiltered from the liquid and the filter cake washed with a small amountof cold (0° C.) heptane. This yielded 2.5 g of2,5-dimethoxy-3,4,6-trimethylbenzaldehyde as a white powder whichyellowed upon storage.

The remaining filtrate was concentrated to a brown oil and purified byflash chromatography (gradient elution, 0-25% EtOAc/heptane) to yield anadditional 4.98 g of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde. Mp84.2-85.4° C.; ¹H NMR (400 MHz, CDCl₃) δ=10.49 (s, 1H), 3.77 (s, 3H),3.65 (s, 3H), 2.50 (s, 3H), 2.21 (s, 3H) ppm.

Step 4: 1-(2,5-Dimethoxy-3,4,6-trimethylphenyl)but-3-en-1-ol

A stirred solution of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde (6.34 g)in 125 mL THF was cooled to 0° C. and treated with 34 mL 1.0 M allylmagnesium bromide (1.0 M in THF, 1.1 equiv.) slowly over 0.25 h viadropping funnel. The solution was stirred for and additional 0.25 h andquenched by the addition of 40 mL 1.0 M aqueous citric acid and stirringuntil the layers clarified. The layers were separated and the aqueouslayer extracted 3×50 mL EtOAc. The combined organics were washed 2×25 mLsaturated aqueous NaCl, dried over Na₂SO₄ and concentrated to yield 9.8g of 1-(2,5-dimethoxy-3,4,6-trimethylphenyl)but-3-en-1-ol as a brownoil. M⁺−H₂O=233.4 m/z; ¹H NMR (400 MHz, CDCl₃) δ=5.90 (m, 1H), 5.15 (m,1H), 5.10 (m, 1H), 4.98 (m, 1H), 3.78 (s, 3H), 3.65 (s, 3H), 2.66 (s,1H), 2.48 (s, 1H), 2.25 (s, 3H), 2.18 (s, 6H) ppm.

Step 5: 1-(But-3-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene

Crude 1-(2,5-dimethoxy-3,4,6-trimethylphenyl)but-3-en-1-ol (9.8 g) in 10mL CH₂Cl₂ was added slowly, dropwise to a rapidly stirred, biphasicsolution of TFA (10.5 mL, 153 mmol, 5 equiv.) and Et₃SiH (6.3 mL, 1.3equiv). The exothermic reaction was cooled in a room temperature waterbath until addition was complete and the reaction stirred for andadditional 2 h at room temperature. The brown solution was concentratedvia rotovap, azeotroped 3×50 mL MeOH and 3×50 mL heptane and remaindertaken up into 100 mL 5% EtOAc/heptane. The organic layer was washed1×100 mL water, 1×50 mL saturated aqueous NaCl, filtered to removeparticulates and dried over Na₂SO₄. Flash chromatography yielded 5.08 gof 1-(but-3-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene as a pale yellowoil which solidified upon standing to an off white wax. ¹H NMR (400 MHz,CDCl₃) δ=5.93 (m, 1H), 5.08 (m, 1H), 4.99 (m, 1H), 3.68 (s, 3H), 3.65(s, 3H), 2.70 (m, 2H), 2.24 (m, 5H), 2.18 (s, 6H) ppm.

Step 6: 4-(2,5-Dimethoxy-3,4,6-trimethylphenyl)butan-1-ol

1-(But-3-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene (5.08 g) in 50 mLTHF was treated with 9-borabicyclo[3.3.1]nonane (9-BBN) (2.96 g) andstirred overnight at room temperature. A chilled solution of 10 M NaOH(10 mL) and 35% w/w H₂O₂ (10 mL) was added to cold borane (0° C.) suchthat the internal temperature never exceeded 36° C. The cloudy solutionwas stirred vigorously and treated with 2 g K₂CO₃ until the layersclarified. Isopropyl acetate (100 mL) was added followed by separationand extraction of the aqueous phase 3×60 mL isopropyl acetate. Thecombined organics were washed with 50 mL saturated NaCl, dried overNa₂SO₄ and concentrated to a pale yellow oil. Flash chromatographyyielded 3.3 g of 4-(2,5-dimethoxy-3,4,6-trimethylphenyl)butan-1-ol as awhite powder (60.3%). Mp 85.1-87.1° C.; ¹H NMR (400 MHz, CDCl₃) δ=3.67(m, 5H), 3.64 (s, 3H), 2.63 (q, 2H), 2.22 (s, 3H), 2.17 (s, 6H), 1.68(m, 2H), 1.55 (m, 2H) ppm.

Step 7:2-(4-(4-Hydroxypiperidin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione

A solution of 4-(2,5-dimethoxy-3,4,6-trimethylphenyl)butan-1-ol (362.9mg) in 5 mL THF was treated with 1,1′-carbonyldiimidazole (CDI) (265 mg,1.2 equiv.) and stirred for 1 h at room temperature. The crudeimidazolidine solution (0.681 mmol) was split into two equal portions(2.5 mL each) and one portion added to 4-hydroxypiperidine (275 mg, 4equiv.) suspended in 4 mL THF. After 16 h, the reaction wasconcentrated, dissolved into 5 mL CH₂Cl₂ washed sequentially with 2.5 mL2.5 M HCl, 5 mL 1 M aqueous NaHCO₃ and 5 mL saturated aqueous NaClbefore drying over Na₂SO₄ and concentration in vacuo to give a yellowoil.

The yellow oil was dissolved into 5 mL MeCN, cooled to 0° C., and 1 Mceric ammonium nitrate (CAN) (2 mL, 2 mmol) added slowly, dropwise untila red color persisted. The reaction was then treated with 5 mL CH₂Cl₂and washed 5×2 mL H₂O and 1×3 mL brine. The aqueous phase wasback-extracted 2×5 mL isopropyl acid/isopropyl acetate (25/75 solution)and the combined organics dried over Na₂SO₄. Flash chromatographyyielded 127.4 mg of2-(4-(4-hydroxypiperidin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dioneas a yellow syrup. M⁺+H at 320 m/z;

¹H NMR (400 MHz, CDCl₃) δ=4.10 (m, 1H), 3.94 (m, 1H), 3.72 (m, 1H), 3.19(m, 2H), 2.53 (m, 2H), 2.39 (t, 2H), 2.06 (s, 3H), 2.01 (s, 6H), 1.89(m, 2H), 1.73 (pent, 2H), 1.52 (m, 2H+H₂O) ppm.

Example 12N-(2-hydroxyethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamideStep 1:4-(2,5-Dimethoxy-3,4,6-trimethylphenyl)-N-(2-hydroxyethyl)butanamide

In 25 mL THF was dissolved4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-butanoic acid (1.32 g, 4.96mmol) prepared as described in Example 1. CDI (884 mg, 5.46 mmol, 1.1equiv.) was added and the solution stirred for 1.75 h at roomtemperature. A small portion (2 mL) was removed for other studies. Theremainder was treated with 370 μL ethanolamine (365 mg, 5.96 mmol, 1.3equiv.) and let stir at room temperature overnight. The clear pale brownsolution was concentrated and the residue dissolved into 100 mLisopropyl acetate and washed with 100 mL 1.25 M HCl, 1×100 mL saturatedaqueous NaCl, 1×50 mL brine and dried over Na2SO4. The reaction mixturewas concentrated yielding 1.15 g of a white powder. M⁺+H at 310 m/z;

¹H NMR (400 MHz, CDCl₃) δ=6.28 (br s, 1H), 3.74 (m, 2H), 3.64 (m, 6H),3.43 (q, 2H), 2.83 (t, 1H), 2.66 (t, 2H), 2.22 (s, 3H), 2.18 (s, 6H),1.85 (pent, 2H) ppm.

Step 2:N-(2-hydroxyethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide

Crude4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-N-(2-hydroxyethyl)butanamide(1.105 g, 3.57 mmol) was taken up into 40 mL MeCN and 2 mL H₂O andcooled to 0° C. To this was added CAN (4.35 g, 7.86 mmol, 2.2 equiv) in5 mL H₂O dropwise over 5 minutes. The reaction was stirred for 0.25 huntil judged complete by HPLC and 50 mL ipropyl acetate was added. Theorganic layer was washed 4×5 mL saturated aqueous NaCl, dried overaqueous Na₂SO₄ and concentrated to a yellow powder. Flash chromatography(gradient elution 80-100% EtOAc/heptane) yielded 619 mg ofN-(2-hydroxyethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamideas a yellow powder. M⁺+H=280 m/z; ¹H NMR (400 MHz, CDCl₃) δ=6.38 (s,1H), 3.77 (t, 2H), 3.47 (m, 2H), 2.54 (t, 2H), 2.29 (t, 2H), 2.05 (s,3H), 2.01 (s, 6H), 1.76 (m, 2H+H₂O) ppm.

Example 13N-Propyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamideStep 1: 2,5-Bis(benzyloxy)-3,4,6-trimethylbenzene

A solution of 2,3,5-trimethylbenzene-1,4-diol (15.2 g, 100 mmol) in DMF(150 mL) was treated with benzyl bromide (35.7 mL, 51.6 g, 300 mmol, 3equiv.) and anhydrous K₂CO₃ (55.3 g, 400 mmol, 4 equiv.). The brownsuspension was heated to 60° C. for 48 h at which time the reaction wasjudged incomplete by HPLC. Additional benzyl bromide (37 mL, 300 mmol, 3equiv.) and K₂CO₃ (50 g, 362 mmol, 3.6 equiv.) were added and heated to60° C. for an additional 48 h. The reaction was cooled, filtered throughCelite, the filter cake rinsed 2×100 mL ethyl acetate and the combinedfiltrates washed with 500 mL H₂O. The aqueous layer was extracted 4×250mL ethylacetate and concentrated at 80° C. by rotary evaporation. Thebrown residue was poured onto 300 mL water which precipitated a lightbrown solid and the resulting suspension stirred overnight. The brownsolid was collected by filtration, washed with 2×50 mL H₂O and dried,yielding 26.8 g of 2,5-bis(benzyloxy)-3,4,6-trimethylbenzene as a brownsolid. ¹H NMR (400 MHz, CDCl₃) δ=7.50-7.34 (m, 10H), 6.64 (s, 1H), 5.03(s, 2H), 4.74 (s, 2H), 2.30 (s, 3H), 2.25 (s, 3H), 2.20 (s, 3H) ppm.

Step 2: 2-Bromo-1,4-bis(benzyloxy)-3,5,6-trimethylbenzene

A solution of 2,5-bis(benzyloxy)-3,4,6-trimethylbenzene in 100 mL DME (5g, 15.0 mmol) was treated with a solution of Br₂ (0.85 mL, 16.5 mmol,1.1 equiv.) in 10 mL DME (1.6 M) over ten minutes. The reaction wasjudged incomplete by HPLC. Additional Br₂ in DME (0.42 mL, 1.31 g, 8.19mmol, 0.55 equiv.) was added and stirred overnight. The reaction wastreated with 200 mL EtOAc, which dissolved the crystals, and washed withH₂O until the aqueous washings were colorless (3×100 mL). The combinedaqueous layers were back extracted with EtOAc (3×50 mL) and the combinedorganics washed 2×100 mL saturated NaCl, dried over Na₂SO₄ andconcentrated to a brown solid. The solid was adsorbed onto silica andpurified by flash chromatography (gradient elution 2-20% EtOAc/heptane)to give a yellow solid. The solid was suspended into heptane, stirredovernight, filtered and the filter cake rinsed with heptane. Theresulting white powder was dried in vacuo and yielded 3.31 g of2-bromo-1,4-bis(benzyloxy)-3,5,6-trimethylbenzene as a white powder. ¹HNMR (400 MHz, CDCl₃) δ=7.57 (d, 2H), 7.48 (d, 2H), 7.44-7.36 (m, 6H),4.87 (s, 2H), 4.74 (s, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H)ppm.

Step 3: 2,5-Bis(benzyloxy)-3,4,6-trimethylbenzaldehyde

To a solution of 2-bromo-1,4-bis(benzyloxy)-3,5,6-trimethylbenzene(5.002 g, 12.16 mmol) in 25 mL toluene and 25 mL Et₂O cooled to 0° C.,was added 8.2 mL n-BuLi (1.6 M in hexanes, 12.76 mmol) over ten minutesto give a clear yellow solution. After 20 min at 0° C. the solution wasbecoming cloudy. To this slightly cloudy solution was added DMF (3 mL,40 mmol, 2.8 g) which clarified the solution instantly upon addition.After overnight stirring, 50 mL 20% aqueous NH₄Cl was added followed by100 mL H₂O and 100 mL EtOAc. The layers were separated and the aqueousphase extracted 3×100 mL EtOAc and the combined organics washed 2×50 mLsaturated aqueous NaCl, dried over Na₂SO₄ and concentrated to yield 3.90g of 2,5-bis(benzyloxy)-3,4,6-trimethylbenzaldehyde as a yellow oilwhich solidified to a pale brown crystalline solid (3.90 g). MS M⁺+H 361m/z; ¹H NMR (400 MHz, CDCl₃) δ=10.51 (s, 1H), 7.51-7.37 (m, 10H), 4.87(s, 2H), 4.74 (s, 2H), 2.55 (s, 3H), 2.30 (s, 3H), 2.25 (s, 3H) ppm plusDMF at 8.01, 2.96, 2.88 and CH₂Cl₂ at 5.30.

Step 4: 1-(2,5-Bis(benzyloxy)-3,4,6-trimethylphenyl)but-3-en-1-ol

2,5-Bis(benzyloxy)-3,4,6-trimethylbenzaldehyde (3.90 g, 12.16 mmol) wasdissolved into 50 mL THF and cooled to 0° C. prior to the addition of 15mL allyl Grignard (1.0 M in THF, 15 mmol). The pale yellow solutionbrowned over the course of the addition. After 15 minutes at 0° C. thereaction was not complete by HPLC and an additional portion of allylGrignard (3 mL, 1.0 M in THF, 3 mmol) was added and stirred for 0.6 h atwhich time the reaction was judged complete by HPLC. The reaction wastreated carefully at 0° C. with 50 mL 10% aqueous NH4Cl stirred for fiveminutes post addition and 100 mL EtOAc added. The layers were stirredvigorously until they clarified, an additional 100 mL H2O and 100 mlEtOAc was added, the layers separated and the aqueous phase extracted3×100 mL EtOAc. The combined organics were washed with 2×50 mL saturatedaqueous NaCl and dried over Na₂SO₄ prior to concentration to a palebrown oil. Storage under vacuum gave a brown solid. Flash chromatography(gradient elution 0-20% EtOAc/heptane) yielded 3.91 g of1-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)but-3-en-1-ol as a white,waxy solid. M⁺+H—H₂O=385 m/z; ¹H NMR (400 MHz, CDCl₃) δ=7.55 (d, 4H),7.51-7.42 (m, 6H), 5.91 (m, 1H), 5.19-5.10 (m, 3H), 5.01 (d, 1H), 4.90(d, 1H), 4.78 (s, 2H), 3.35 (d, 1H), 2.76 (m, 1H), 2.55 (m, 1H), 2.39(s, 3H), 2.32 (s, 3H), 2.31 (s, 3H) ppm.

Step 5: 1-(2,5-Bis(benzyloxy)-3,4,6-trimethylphenyl)-3-butene

1-(2,5-Bis(benzyloxy)-3,4,6-trimethylphenyl)but-3-en-1-ol (3.7 g, 9.4mmol) was dissolved into 10 mL CH₂Cl₂ and treated with Et₃SiH (12 mL,94.4 mmol.). To this clear, colorless solution was added trifluoroaceticacid (TFA) (10.5 mL, 142 mmol) neat over 3 minutes which darkened thesolution and exothermed. The reaction vessel was placed in a roomtemperature water bath and let stir for 1.25 h. The reaction wasconcentrated to yellow oil via rotary evaporation and the residuedissolved in 100 mL methyl t-butyl ether (MTBE). To this was added 50 mL2.5 M K₂CO₃, the layers separated and the aqueous phase extracted 3×50mL MTBE. The combined organics were washed with 50 mL saturated aqueousNaCl, dried over Na₂SO₄ and concentrated to give1-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)-3-butene, (3.6 g) as ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ=7.51 (d, 4H), 7.44-7.35 (m, 6H),5.90 (m, 1H), 5.06 (d, 1H), 4.97 (d, 1H), 4.78 (s, 2H), 4.74 (s, 2H),2.74 (m, 2H), 2.27-2.24 (m, 9H) ppm.

Step 6: 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)butan-1-ol

1-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)-3-butene (1.1 g, 2.85 mmol)in THF (15 mL) was treated with 9-BBN (560 mg, 4.27 mmol, 1.5 equiv.) atroom temperature. After 2.5 h the clear colorless solution was treatedwith 2.5 M aqueous NaOH (6 mL, 15 mmol), was added followed by slow,dropwise addition of 35% w/w H₂O₂ (5 mL, 58.5 mmol). During addition,the internal reaction temperature was kept below 35° C. by ice bathimmersion. The biphasic solution was stirred for 1.5 h at roomtemperature, 35 mL isopropyl acetate added and the layers separated. Theaqueous phase was extracted 3×25 mL isopropyl acetate and the combinedorganics washed 2×25 mL saturated aqueous NaCl and dried over Na₂SO₄.Flash chromatography (gradient elution 10-60% EtOAc/heptane) yielded 741mg of 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)butan-1-ol as a clearcolorless oil. M⁺+H at 405 m/z;

¹H NMR (400 MHz, CDCl₃) δ=7.50 (d, 4H), 7.44-7.35 (m, 6H), 4.76 (s, 2H),4.74 (s, 2H), 3.62 (q, 2H), 2.68 (m, 2H), 2.26 (s, 3H), 2.40-2.23 (m,6H), 1.61 (m, 2H+2) ppm.

Step 7: 4-(2,5-Bis(benzyloxy)-3,4,6-trimethylphenyl)butanal

A stirred solution of4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)butan-1-ol (640 mg, 1.58mmol) in 10 mL CH₂Cl₂ at 0° C. was treated with a suspension ofDess-martin periodonate (860 mg, 2.03 mmol) in CH₂Cl₂ (4 mL) and thepale yellow cloudy solution stirred at room temperature for 1.25 h. Thecloudy white solution was poured over a solution of 10 mL 1.0 M NaHCO₃containing ˜0.5 g Na₂S₂O₃ and 20 mL EtOAc added, the layers separatedand the aqueous phase extracted 3×20 mL EtOAc. The combined organicswere washed with 20 mL saturated aqueous NaCl, dried over Na₂SO₄ andconcentrated to a yellow-white solid. The solid was dissolved into 5 mLEtOAc, filtered and the residual solids rinsed with EtOAc. The combinedwashings were stored overnight at 2° C., concentrated and purified byflash chromatography (gradient elution, 0-20% EtOAc/heptanes) collecting530 mg of 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)butanal. MS M⁺+Hat 403 m/z; ¹H NMR (400 MHz, CDCl₃) δ=9.67 (t, 1H), 7.52-7.48 (m, 2H),7.45-7.36 (m, 6H), 4.75 (s, 2H), 4.74 (s, 2H), 2.69 (t, 2H), 2.44 (td,2H), 2.27 (s, 3H), 2.24 (s, 6H), 1.84 (pent, 2H) ppm.

Step 8: 4-(2,5-Bis(benzyloxy)-3,4,6-trimethylphenyl)butanoic acid

To a solution of 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)butanal(450 mg, 1.12 mmol) in DMF (11.5 mL) was added Oxone (350 mg, 1.12 mmol)giving a cloudy white solution. The suspension was stirred vigorouslyovernight and poured over 10 mL 2.5 M HCl and stirred until the solutionclarified. Isopropyl acetate (iPrOAc) (25 mL) was added after theexotherm subsided. The organics were washed 2×10 mL 2.5 M HCl, 1×10 mLsaturated aqueous NaCl and dried over Na₂SO₄. Concentration gave 435 mgof 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)butanoic acid as a whitesolid. MS M⁺+H at 419 m/z; ¹H NMR (400 MHz, CDCl₃) δ=7.50 (m, 4H),7.43-7.34 (m, 6H), 4.75 (s, 2H), 4.74 (s, 2H), 2.71 (t, 2H), 2.37 (t,2H), 2.26 (s, 3H), 2.26 (s, 6H), 1.85 (s, 2H) ppm.

Step 9: 4-(2,5-Bis(benzyloxy)-3,4,6-trimethylphenyl)-N-propylbutanamide

A solution of 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)butanoic acid(325 mg) in 3 mL THF was treated with carbonyldiimidazole (177 mg, 1.06mmol). The cloudy yellow solution was stirred at room temperature for1.5 h. One portion of ˜0.45 mmol was added to a solution ofn-propylamine (155 μL, 111 mg) in 2 mL THF and let stir overnight. Thereaction mixture was concentrated to a pink-tan solid, dissolved into 5mL CH₂Cl₂ and washed with 1×3 mL 2.5 M HCl, 1×3 mL saturated aqueousNaHCO3, 2×2 mL saturated aqueous NaCl, dried over Na2SO4 andconcentrated to yield 117 mg of4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)-N-propylbutanamide as awhite powder. MS M⁺+H at 460 m/z; ¹H NMR (400 MHz, CDCl₃) δ=7.50 (m,4H), 7.44-7.35 (m, 6H), 5.47 (br m, 1H), 4.74 (s, 2H), 4.73 (s, 2H),3.03 (q, 2H), 2.70 (t, 2H), 2.27 (s, 3H), 2.25 (s, 3H), 2.23 (s, 3H),2.14 (t, 2H), 1.84 (pent, 2H), 1.39 (m, 2H), 0.84 (t, 3H) ppm.

Step 10:N-Propyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide

A stirred solution of4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)-N-propylbutanamide (176.6mg) in TFA (2 mL) was treated with Pd/C (40 mg, 5% Pd by wt), spargedwith H2 and heated to 40° C. for 2.25 h. The reaction was cooled,diluted with CH₂Cl₂, (4 mL) filtered and the solids washed 2×3 mL CH₂Cl₂before concentration to a brown oil which solidified upon standing. Thecrude hydroquinone was dissolved into 1 mL MeCN and 1.5 mL 1 M aqueousCAN added (1.5 mmol, 3.9 equiv.). After 0.25 h, 5 mL EtOAc was added andthe organics washed with 4×3 mL saturated NaCl (aq). The combinedaqueous layers were back-extracted 2×3 mL EtOAc, the combined organicsdried over Na2SO4, concentrated and purified by flash chromatography(gradient elution, 10-50% EtOAc/heptane) yieldingN-propyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide asa yellow solid (78.0 mg), MS M⁺+H 278; ¹H NMR (400 MHz, CDCl₃) δ=5.83(m, 1H), 3.24 (q, 2H), 2.50 (t, 2H), 2.22 (t, 2H), 2.08 (s, 3H), 1.97(s, 6H), 1.71 (pent, 2H), 1.54 (m, 2H), 0.92 (t, 3H) ppm.

Biological Examples Example A Screening Compounds of the Invention inHuman Dermal Fibroblasts from Friedreich's Ataxia Patients

An initial screen was performed to identify compounds effective for theamelioration of redox disorders. Test samples, 4 reference compounds(Idebenone, decylubiquinone, Trolox and α-tocopherol acetate), andsolvent controls were tested for their ability to rescue FRDAfibroblasts stressed by addition of L-buthionine-(S,R)-sulfoximine(BSO), as described in Jauslin et al., Hum. Mol. Genet. 11(24):3055(2002), Jauslin et al., FASEB J. 17:1972-4 (2003), and InternationalPatent Application WO 2004/003565. Human dermal fibroblasts fromFriedreich's Ataxia patients have been shown to be hypersensitive toinhibition of the de novo synthesis of glutathione (GSH) withL-buthionine-(S,R)-sulfoximine (BSO), a specific inhibitor of GSHsynthetase (Jauslin et al., Hum. Mol. Genet. 11(24):3055 (2002)). Thisspecific BSO-mediated cell death can be prevented by administration ofantioxidants or molecules involved in the antioxidant pathway, such asα-tocopherol, selenium, or small molecule glutathione peroxidasemimetics. However, antioxidants differ in their potency, i.e. theconcentration at which they are able to rescue BSO-stressed FRDAfibroblasts.

MEM (a medium enriched in amino acids and vitamins, catalog no.1-31F24-I) and Medium 199 (M199, catalog no. 1-21F22-I) with Earle'sBalanced Salts, without phenol red, were purchased from Bioconcept.Fetal Calf Serum was obtained from PAA Laboratories. Basic fibroblastgrowth factor and epidermal growth factor were purchased from PeproTech.Penicillin-streptomycin-glutamine mix, L-buthionine (S,R)-sulfoximine,(+)-α-tocopherol acetate, decylubiquinone, and insulin from bovinepancreas were purchased from Sigma. Trolox(6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid) was obtainedfrom Fluka. Idebenone was obtained from Chemo Iberica. Calcein AM waspurchased from Molecular Probes. Cell culture medium was made bycombining 125 ml M199 EBS, 50 ml Fetal Calf Serum, 100 U/ml penicillin,100 μg/ml streptomycin, 2 mM glutamine, 10 μg/ml insulin, 10 ng/ml EGF,and 10 ng/ml bFGF; MEM EBS was added to make the volume up to 500 ml. A10 mM BSO solution was prepared by dissolving 444 mg BSO in 200 ml ofmedium with subsequent filter-sterilization. During the course of theexperiments, this solution was stored at +4° C. The cells were obtainedfrom the Coriell Cell Repositories (Camden, N.J.; repository numberGM04078) and grown in 10 cm tissue culture plates. Every third day, theywere split at a 1:3 ratio.

The test samples were supplied in 1.5 ml glass vials. The compounds werediluted with DMSO, ethanol or PBS to result in a 5 mM stock solution.Once dissolved, they were stored at −20° C. Reference antioxidants(Idebenone, decylubiquinone, α-tocopherol acetate and trolox) weredissolved in DMSO.

Test samples were screened according to the following protocol:

A culture with FRDA fibroblasts was started from a 1 ml vial withapproximately 500,000 cells stored in liquid nitrogen. Cells werepropagated in 10 cm cell culture dishes by splitting every third day ina ratio of 1:3 until nine plates were available. Once confluent,fibroblasts were harvested. For 54 micro titer plates (96 well-MTP) atotal of 14.3 million cells (passage eight) were re-suspended in 480 mlmedium, corresponding to 100 μl medium with 3,000 cells/well. Theremaining cells were distributed in 10 cm cell culture plates (500,000cells/plate) for propagation. The plates were incubated overnight at 37°C. in an atmosphere with 95% humidity and 5% CO₂ to allow attachment ofthe cells to the culture plate.

MTP medium (243 μl) was added to a well of the microtiter plate. Thetest compounds were unfrozen, and 7.5 μl of a 5 mM stock solution wasdissolved in the well containing 243 μl medium, resulting in a 150 μMmaster solution. Serial dilutions from the master solution were made.The period between the single dilution steps was kept as short aspossible (generally less than 1 second).

Plates were kept overnight in the cell culture incubator. The next day,10 μl of a 10 mM BSO solution were added to the wells, resulting in a 1mM final BSO concentration. Forty-eight hours later, three plates wereexamined under a phase-contrast microscope to verify that the cells inthe 0% control (wells E1-H1) were clearly dead. The medium from allplates was discarded, and the remaining liquid was removed by gentlytapping the plate inversed onto a paper towel.

100 μl of PBS containing 1.2 μM Calcein AM were then added to each well.The plates were incubated for 50-70 minutes at room temperature. Afterthat time the PBS was discarded, the plate gently tapped on a papertowel and fluorescence (excitation/emission wavelengths of 485 nm and525 nm, respectively) was read on a Gemini fluorescence reader. Data wasimported into Microsoft Excel (EXCEL is a registered trademark ofMicrosoft Corporation for a spreadsheet program) and used to calculatethe EC₅₀ concentration for each compound.

The compounds were tested three times, i.e., the experiment wasperformed three times, the passage number of the cells increasing by onewith every repetition.

The solvents (DMSO, ethanol, PBS) neither had a detrimental effect onthe viability of non-BSO treated cells nor did they have a beneficialinfluence on BSO-treated fibroblasts even at the highest concentrationtested (1%). None of the compounds showed auto-fluorescence. Theviability of non-BSO treated fibroblasts was set as 100%, and theviability of the BSO- and compound-treated cells was calculated asrelative to this value.

The following table summarizes the EC₅₀ for the four control compounds.

EC₅₀ [μM] Value Value Value Compound 1 2 3 Average Stdev Decylubiquinone0.05 0.035 0.03 0.038 0.010 alpha-Tocopherol acetate 0.4 0.15 0.35 0.300.13 Idebenone 1.5 1 1 1.2 0.3 Trolox 9 9 8 8.7 0.6

Certain compounds of the present invention such as:

-   1-(2-hydroxyethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(2-(dimethylamino)ethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   4-fluoro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzenesulfonamide;-   3-(2-(dimethylamino)ethyl)-1-methyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   3-ethyl-1-methyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   N-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-4-fluorobenzenesulfonamide;-   1-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-3-ethylurea;-   N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;    4-methoxy-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzenesulfonamide;-   1-(2-morpholinoethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   4-benzyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;-   N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;-   1-(4-chlorobenzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   4-methyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;-   4-chloro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   4-fluoro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   4-(trifluoromethyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   2-(4-chlorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   2-(4-fluorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-diethyl)ethyl)acetamide;-   1-(4-fluorobenzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   N-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-4,4-difluorocyclohexanecarboxamide;-   2-(4-chorophenyl)-N-methyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   2-(4-methoxyphenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   4-acetyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   4-methyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   4-cyano-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   1-phenyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-cyclopropanecarboxamide;-   1-(4-methoxyphenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)cyclopropanecarboxamide;-   2-(naphthalen-1-yl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   2-(2-methoxyphenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   3-(4-fluorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)propanamide;-   2-hydroxy-2-phenyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   2-(4-chlorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)propanamide;-   2-(4-fluorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)propanamide;-   2-hydroxy-2-(4-(trifluoromethyl)phenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   1-(4-(trifluoromethyl)benzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(pyridin-4-ylmethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   3-ethyl-1-methyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(pyridin-3-ylmethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-4-methylbenzenesulfonamide;-   N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)methanesulfonamide;-   N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   1-ethyl-3-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   5-(1,2-dithiolan-3-yl)-N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)pentanamide;-   N-(2-hydroxyethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-methoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-p-tolyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,4-dimethoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-(trifluoromethyl)phenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    -   N-(benzo[d][1,3]dioxol-5-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-methoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-methoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,3-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,5-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,4-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,5-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(pyridin-3-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(pyridin-4-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-hydroxyethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-methyl-N-phenethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorophenyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,6-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(pyridin-2-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-cyanophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,5-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,6-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,4-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,5-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-methyl-N-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-chlorophenyl)-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorophenyl)-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-cyanophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(pyridin-3-ylmethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-(pyridin-4-yl)ethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-aminophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-amino-4-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-methyl-N-(pyridin-2-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-chlorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-chlorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-chlorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-chlorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-(4-(indolin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(isoindolin-2-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene    1,4-dione;-   2-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(3,4-dihydroquinolin-1(2H)-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   N-(3-cyanophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-N-ethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-N-isopropyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-((1-hydroxycyclopropyl)methyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2,3,5-trimethyl-6-(4-oxo-4-(pyrrolidin-1-yl)butyl)cyclohexa-2,5-diene-1,4-dione;-   N-(1-hydroxy-2-methylpropan-2-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-(4-(4-hydroxypiperidin-1-yl)-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;    and-   2,2-dimethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    exhibited protection against FRDA with an EC₅₀ of less than about    150 nM.

Example B Screening Compounds of the Invention in Fibroblasts fromHuntington's Patients

Compounds of the invention were tested using the screen as described inExample A, but substituting FRDA cells with Huntington's cells obtainedfrom the Coriell Cell Repositories (Camden, N.J.; repository number GM04281). The compounds were tested for their ability to rescue humandermal fibroblasts from Huntington's patients from oxidative stress.

Certain compounds of the present invention such as:

-   1-(2-hydroxyethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(2-(dimethylamino)ethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   4-fluoro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzenesulfonamide;-   3-(2-(dimethylamino)ethyl)-1-methyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   N-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-4-fluorobenzenesulfonamide;-   1-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   4-methoxy-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzenesulfonamide;-   1-(2-morpholinoethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   4-benzyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;-   1-(4-chlorobenzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   4-methyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;-   4-acetyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;-   4-oxo-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;-   2-(4-chlorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   2-(4-fluorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   1-(4-fluorobenzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   2-(4-chlorophenyl)-N-methyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   2-(4-methoxyphenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   4-acetyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   4-methyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   2-(4-chlorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)propanamide;-   2-hydroxy-2-(4-(trifluoromethyl)phenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   1-(4-chlorobenzyl)-1-methyl-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   2-(4-chlorophenyl)-2-hydroxy-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   1-(pyridin-4-yl    methyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(pyridin-3-ylmethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(4-(trifluoromethyl)benzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-4-methylbenzenesulfonamide;-   N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)methanesulfonamide;-   N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   1-ethyl-3-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   5-(1,2-dithiolan-3-yl)-N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)pentanamide;-   N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)hexanamide;-   N-(2-hydroxyethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-phenethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-methoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-p-tolyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,4-dimethoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-(trifluoromethyl)phenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(benzo[d][1,3]dioxol-5-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-methoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-methoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,3-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,5-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,4-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,5-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    N-(pyridin-3-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(pyridin-4-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-hydroxyethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-methyl-N-phenethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorophenyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,6-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien    yl)butanamide;-   N-(pyridin-2-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-cyanophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,5-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,6-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,4-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,5-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-methyl-N-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-chlorophenyl)-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorophenyl)-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-cyanophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(pyridin-3-ylmethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-(pyridin-2-yl)ethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-(pyridin-4-yl)ethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-aminophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-(4-(4-fluoropiperidin-1-yl)-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-methyl-N-propyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-amino-4-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-methyl-N-(pyridin-2-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-chlorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-chlorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-chlorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-fluorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-fluorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-chlorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-chlorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-chlorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-(4-(indolin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(isoindolin-2-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(3,4-dihydroisoquinolin-2(1)-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(3,4-dihydroquinolin-1    (2H)-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   N-(3-cyanophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-N-ethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-N-isopropyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-((1-hydroxycyclopropyl)methyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    and-   2,2-dimethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    exhibited protection against Huntington's with an EC₅₀ of less than    about 150 nM.

Example C Screening Compounds of the Invention in Fibroblasts fromLeber's Hereditary Optic Neuropathy Patients

Compounds of the invention were screened as described in Example A, butsubstituting FRDA cells with Leber's Hereditary Optic Neuropathy (LHON)cells obtained from the Coriell Cell Repositories (Camden, N.J.;repository number GM03858). The compounds were tested for their abilityto rescue human dermal fibroblasts from LHON patients from oxidativestress.

Certain compounds of the present invention such as:

-   1-(2-hydroxyethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(2-(dimethylamino)ethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   4-fluoro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzenesulfonamide;-   3-(2-(dimethylamino)ethyl)-1-methyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-3-ethylurea;-   N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   4-methoxy-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzenesulfonamide;-   1-(2-morpholinoethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   4-benzyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;-   4-hydroxy-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;-   1-(4-chlorobenzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   4-methyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;-   4-acetyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;-   4-oxo-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;-   N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)nicotinamide;-   4-chloro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   4-fluoro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   4-(trifluoromethyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   2-(4-chlorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   2-(4-fluorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   1-(4-fluorobenzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   N-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-4,4-difluorocyclohexanecarboxamide;-   2-(4-chlorophenyl)-N-methyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   2-(4-methoxyphenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   4-acetyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   4-methyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   4-cyano-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   1-phenyl-N′-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)cyclopropanecarboxamide;-   2-hydroxy-2-phenyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   2-hydroxy-2-(4-(trifluoromethyl)phenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   1-(4-chlorobenzyl)-1-methyl-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   2-(4-chlorophenyl)-2-hydroxy-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   1-(pyridin-4-ylmethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(pyridin-3-ylmethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(4-(trifluoromethyl)benzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-4-methylbenzenesulfonamide;-   N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)methanesulfonamide;-   N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   1-ethyl-3-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   5-(1,2-dithiolan-3-yl)-N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)pentanamide;-   N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)hexanamide;-   N-(2-hydroxyethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-(4-(4-benzoylpiperazin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(4-(cyclohexanecarbonyl)piperazin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   N-phenethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-(4-(4-fluoropiperidin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(4,4-difluoropiperidin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   N-(4-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-methoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-p-tolyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,4-dimethoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-(trifluoromethyl)phenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(benzo[d][1,3]dioxol-5-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-methoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-methoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,3-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,5-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,4-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,5-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    N-(pyridin-3-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(pyridin-4-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-hydroxyethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-methyl-N-phenethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorophenyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,6-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(pyridin-2-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-cyanophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,5-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,6-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,4-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,5-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-methyl-N-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-chlorophenyl)-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorophenyl)-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-cyanophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(pyridin-3-ylmethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-(pyridin-2-yl)ethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-(pyridin-4-yl)ethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-aminophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-(4-(4-fluoropiperidin-1-yl)-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   N-(2-amino-4-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-methyl-N-(pyridin-2-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-chlorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-chlorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-chlorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-chlorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-chlorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-chlorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-(4-(indolin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(isoindolin-2-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(3,4-dihydroquinolin-1(2H)-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   N-(3-cyanophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-N-ethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-N-isopropyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-((1-hydroxycyclopropyl)methyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    and-   2,2-dimethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    exhibited protection against LHON with an EC₅₀ of less than about    150 nM.

Example D Screening Compounds of the Invention in Fibroblasts fromParkinson's Disease Patients

Compounds of the invention were screened as described in Example A, butsubstituting FRDA cells with Parkinson's Disease (PD) cells obtainedfrom the Coriell Cell Repositories (Camden, N.J.; repository numberAG20439). The compounds were tested for their ability to rescue humandermal fibroblasts from Parkinson's Disease patients from oxidativestress.

Certain compounds of the present invention such as

-   1-(2-hydroxyethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(2-(dimethylamino)ethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   4-fluoro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzenesulfonamide;-   N-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-4-fluorobenzenesulfonamide;-   1-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   4-methoxy-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzene    sulfonamide;-   4-benzyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;-   1-(4-chlorobenzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   4-chloro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   4-fluoro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   4-(trifluoromethyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   2-(4-chlorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   2-(4-fluorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   1-(4-fluorobenzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   1-(pyridin-4-ylmethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(pyridin-3-ylmethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   N-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    -   N-(4-methoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-p-tolyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,4-dimethoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-(trifluoromethyl)phenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(benzo[d][1,3]dioxol-5-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-methoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-methoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,3-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,5-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,4-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(pyridin-4-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,6-dichlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(pyridin-2-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-cyanophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,5-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,6-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,4-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,5-difluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-methyl-N-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-chlorophenyl)-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorophenyl)-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-amino-4-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-methyl-N-(pyridin-2-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-chlorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-chlorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-chlorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-fluorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-fluorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-chlorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-chlorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-chlorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-(4-(indolin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(isoindolin-2-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   N-benzyl-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-N-ethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-N-isopropyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(1-hydroxy-2-methylpropan-2-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    and-   2,2-dimethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    exhibited protection against PD with an EC₅₀ of less than about 150    nM.

Example E Screening Compounds of the Invention in Fibroblasts from CoQ10Deficient Patients

Compounds of the invention were tested using a screen similar to the onedescribed in Example A, but substituting FRDA cells with cells obtainedfrom CoQ10 deficient patients harboring a CoQ2 mutation. The compoundswere tested for their ability to rescue human dermal fibroblasts fromCoQ10 deficient patients from oxidative stress.

Certain compounds of the present invention such as:

-   4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   4-cyano-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)benzamide;-   1-phenyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)cyclopropanecarboxamide;-   1-(4-methoxyphenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)cyclopropanecarboxamide;-   2-(4-methoxyphenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   2-(naphthalen-1-yl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   2-(2-methoxyphenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   3-(4-fluorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)propanamide;-   2-(4-chlorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)propanamide;-   2-(4-fluorophenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)propanamide;-   2-hydroxy-2-(4-(trifluoromethyl)phenyl)-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)acetamide;-   1-(4-chlorobenzyl)-1-methyl-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   1-(4-(trifluoromethyl)benzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;-   N-phenethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-p-tolyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3,4-dimethoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-(trifluoromethyl)phenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(benzo[d][1,3]dioxol-5-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-methoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-methoxyphenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-fluorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-cyanophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-methyl-N-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-chlorophenyl)-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorophenyl)-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-amino-4-chlorophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-chlorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-chlorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-chlorophenethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-fluorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-fluorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-fluorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(2-chlorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(3-chlorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-(4-chlorobenzyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   2-(4-(indolin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(isoindolin-2-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   2-(4-(3,4-dihydroquinolin-1(2H)-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;-   N-(3-cyanophenyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-N-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-N-ethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-benzyl-N-isopropyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;-   N-((1-hydroxycyclopropyl)methyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    and-   2,2-dimethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;    exhibited protection against CoQ10 deficiency with an EC₅₀ of less    than about 150 nM.

Example F In Vitro System for Drug Ototoxicity Screening

The conditionally immortalized auditory HEI-OC1 cells from long-termcultures of transgenic mice Immortomouse™ cochleas as described inKalinec, G. et al., Audiol. Nerootol. 2003; 8, 177-189/. were maintainedin high glucose Dulbecco's modified Eagle medium (DMEM) containing 10%FBS under permissive conditions, 33° C., 10% CO2. Cells were pretreatedovernight with compounds, and apoptosis was detected by caspase3/7activity after 24 hours of 50 uM cisplatin incubation. Cells incubatedin diluent alone were the controls.

Example G Screening Compounds of the Invention in Human DermalFibroblasts from Autistic Patients

A screen is performed to identify compounds effective for theamelioration of ASD. Test samples, and solvent controls are tested fortheir ability to rescue ASD fibroblasts stressed by addition ofL-buthionine-(S,R)-sulfoximine (BSO).

MEM (a medium enriched in amino acids and vitamins, catalog no. Gibco11965) and Fetal Calf Serum are obtained from Invitrogen. Basicfibroblast growth factor and epidermal growth factor are purchased fromPeproTech. Penicillin-streptomycin-glutamine mix, L-buthionine(S,R)-sulfoximine, and insulin from bovine pancreas are purchased fromSigma. Calcein AM is purchased from Molecular Probes. Cell culturemedium (ATP) is made by combining 75 ml Fetal Calf Serum, 100 U/mlpenicillin, 100 μg/ml streptomycin, 2 mM glutamine, 10 ng/ml EGF, and 10ng/ml bFGF; MEM EBS is added to make the volume up to 500 ml. A 10 mMBSO solution is prepared by dissolving 444 mg BSO in 200 ml of mediumwith subsequent filter-sterilization. During the course of theexperiments, this solution is stored at +4° C. The cells obtained fromDr. J. M. Shoffner, Medical Neurogenetics, Atlanta, Ga. are grown in 10cm tissue culture plates. Every week, they are split at a 1:3 ratio.

The samples are supplied in 1.5 ml glass vials. The compounds arediluted with DMSO, ethanol or PBS to result in a 5 mM stock solution.Once dissolved, they are stored at −20° C.

The samples are screened according to the following protocol:

A culture with ASD fibroblasts is started from a 1 ml vial withapproximately 500,000 cells stored in liquid nitrogen. Cells arepropagated in 10 cm cell culture dishes by splitting every week in aratio of 1:3 until nine plates are available. Once confluent,fibroblasts are harvested. For 54 micro titer plates (96 well-MTP) atotal of 14.3 million cells (passage eight) are re-suspended in 480 mlmedium, corresponding to 100 μl medium with 3,000 cells/well. Theremaining cells are distributed in 10 cm cell culture plates (500,000cells/plate) for propagation. The plates are incubated overnight at 37°C. in an atmosphere with 95% humidity and 5% CO2 to allow attachment ofthe cells to the culture plate.

MTP medium (243 μl) is added to a well of the microtiter plate. The testcompounds are unfrozen, and 7.5 μl of a 5 mM stock solution is dissolvedin the well containing 243 μl medium, resulting in a 150 μM mastersolution. Serial dilutions from the master solution are made. The periodbetween the single dilution steps is kept as short as possible(generally less than 1 second).

Plates are kept overnight in the cell culture incubator. The next day,10 μl of a 10 mM BSO solution are added to the wells, resulting in a 1mM final BSO concentration. Forty-eight hours later, three plates areexamined under a phase-contrast microscope to verify that the cells inthe 0% control (wells E1-H1) are clearly dead. The medium from allplates is discarded, and the remaining liquid is removed by gentlytapping the plate inversed onto a paper towel.

100 μl of PBS containing 1.2 μM Calcein AM are then added to each well.The plates are incubated for 50-70 minutes at room temperature. Afterthat time the PBS is discarded, the plate gently tapped on a paper toweland fluorescence (excitation/emission wavelengths of 485 nm and 525 nm,respectively) is read on a Gemini fluorescence reader. Data was importedinto Microsoft Excel® and used to calculate the EC₅₀ concentration foreach compound.

The compounds are tested three times, i.e., the experiment is performedthree times, the passage number of the cells increasing by one withevery repetition.

The solvents (DMSO, ethanol, PBS) neither have a detrimental effect onthe viability of non-BSO treated cells nor do they have a beneficialinfluence on BSO-treated fibroblasts even at the highest concentrationtested (1%). None of the compounds show auto-fluorescence. The viabilityof non-BSO treated fibroblasts is set as 100%, and the viability of theBSO- and compound-treated cells is calculated as relative to this value.

Certain compounds of the present invention are considered to be activeif they exhibit protection against ASD with an EC50 of less than 300 nM.

The disclosures of all publications, patents, patent applications andpublished patent applications referred to herein by an identifyingcitation are hereby incorporated herein by reference in their entirety.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

What is claimed is:
 1. A compound of Formula I:

where, R is selected from the group consisting of:

where the * indicates the point of attachment of R to the remainder ofthe molecule; M and M′ are independently selected from the groupconsisting of hydrogen, —C(O)—R′, —C(O)—(C₂-C₆)-alkenyl,—C(O)—(C₂-C₆)-alkynyl, —C(0)-aryl, —C(O)—heterocyclyl, —C(O)O—R′,—C(O)NR′R″, —SO₂OR′, —SO₂(C₁-C₆)-alkyl, —SO₂(C₁-C₆)-haloalkyl,—SO₂-aryl, —SO₂NR′R″, —P(O)(OR′)(OR″), and C-linked mono-or di-peptide,where R′ and R″ are independently of each other hydrogen or(C₁-C₆)-alkyl optionally substituted with one or more substituentsindependently selected from the group consisting of —OH, —NH₂,—NH(C₁-C₄)-alkyl, —N((C₁-C₄)-alkyl)₂, —C(O)OH, —C(O)O—(C₁-C₄)-alkyl, andhalogen; R¹ is (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, heterocyclyl, or aryl,where the heterocyclyl and the aryl are optionally substituted with oneor more substituents independently selected from the group consisting of—OH, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, hydroxyl-(C₁-C₆)alkyl-,alkoxy(C₁-C₆)-alkyl-, —NR¹⁰R^(10′), —(C₁-C₆)-alkyl —NR¹⁰R^(10′),—C(O)—(C₁-C₆)-alkyl, —C(O)—OH, —C(O)O—(C₁-C₆)-alkyl,—C(O)NR¹⁰R^(10′),—NR¹¹C(O)R¹⁰, —NR¹¹C(O)NR¹⁰R¹⁰—NR¹¹(C(O)OR¹⁰, —SO₂(C₁-C₆)-alkyl, —SO₂(C₁-C₆)-haloalkyl, —SO₂-aryl, —SO₂NR¹⁰R^(10′), CN, haloalkyl, andhalogen; R² is hydrogen, (C₁-C₆)-alkyl, or (C₁-C₆)-alkoxy; R³ isunsubstituted (C₁-C₆)-alkyl; R⁴ is hydrogen or (C₁-C₆)-alkyl; R⁵ is—C(O)NR⁶R⁷; R⁶ is hydrogen, (C₁-C₆)-alkyl, aryl, or heterocyclyl, where(C₁-C₆)-alkyl is optionally substituted with one or more substituentsindependently selected from the group consisting of: —OR¹¹, —SR¹¹, —CN,—F, —Cl, —Br, —I, —NR¹⁰R^(10′), (C₃-C₆)-cycloalkyl, aryl, heterocyclyl,—C(O)—R¹¹, —C(O)—(C₀-C₆)-alkyl-aryl, —C(O)O—R¹¹,—C(O)—O—(C₀-C₆)-alkyl-aryl, —C(O)N—R¹⁰R^(10′),C(O)NR¹¹-(C₀-C₆)-alkyl-aryl, —NR¹¹C(O)—R¹⁰, and—NR¹¹C(O)—(C₀-C₆)-alkyl-aryl; wherein the aryl and heterocyclyl ringsubstituents may be further substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)-alkyl,halogen, (C₁-C₆) -haloalkyl, CN, oxo, hydroxy, (C₁-C₆)-alkoxy,—C(O)—(C₁-C₆) -alkyl, and —C(O)—O—(C₁-C₆)-alkyl; and where aryl andheterocyclyl are optionally substituted with (C₁-C₆)-alkyl, halogen,(C₁-C₆)-haloalkyl, CN, oxo, hydroxy, (C₁-C₆)-alkoxy, —C(O)—(C₁-C₆)-alkylor —C(O)—O—(C₁-C₆)-alkyl; R⁷ is hydrogen or (C₁-C₆)-alkyl; or R⁶ and R⁷together with the atom to which they are attached form a saturated orunsaturated 3-8 membered ring, optionally incorporating one, two, orthree additional heteroatoms independently selected from the groupconsisting of N, O, and S atoms, and optionally substituted with oxo,—OH, —SH, —F, —Cl, —Br, —I, —NR¹¹R^(11′), (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,(C₁-C₆)-thioalkyl, (C₁-C₆)-haloalkyl, hydroxy-(C₁-C₆)-alkyl, —C(O)—H,—C(O)—(C₁-C₆)-alkyl, —C(O)OH, or —C(O)O—(C₁-C₆)-alkyl; R¹⁰ and R^(10′)are independently selected from the group consisting of H,(C₁-C₆)-alkyl, (C₁-C₆) -haloalkyl, aryl, -aryl-(C₁-C₆)-alkyl,heteroaryl, heterocyclyl, —C(O)—H, —C(O)—(C₁-C₆)-alkyl, —C(O)-aryl, and—C(O)—(C₁-C₆)-alkyl-aryl; or R¹⁰ and R^(10′) together with the atom towhich they are attached form a saturated or unsaturated 3-8 memberedring, optionally incorporating one, two, or three additional heteroatomsindependently selected from the group consisting of N, O, and S atoms,and optionally substituted with one or more substituents independentlyselected from the group consisting of oxo, —OH, —F,—Cl, —Br, —I,—NR¹¹R^(11′), (C₁ C₆)-alkyl, (C₁-C₆)-alkoxy, (C₁-C₆)-haloalkyl, hydroxy-(C₁-C₆)-alkyl-, —C(O)—H, —C(O )—(C₁-C₆)-alkyl, —C(O)OH, and—C(O)O—(C₁-C₆)-alkyl; R¹¹ and R^(11′) are independently selected fromthe group consisting of hydrogen and (C₁-C₆)-alkyl; and A is(C₁-C₄)-alkylene, (C₂-C₄)-alkenylene, or (C₂-C₄)-alkynylene; or a salt,a stereoisomer, or a mixture of stereoisomers thereof.
 2. The compoundof claim 1 of Formula Ia:

where, R¹ is (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, heterocyclyl, or aryl, wherethe heterocyclyl and the aryl are optionally substituted with one ormore substituents independently selected from the group consisting of—OH, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, hydroxy-(C₁-C₆)alkyl-,alkoxy(C₁-C₆)alkyl-, —NR¹⁰R^(11′), —(C₁-C₆)-alkyl —NR¹⁰R^(10′),—C(O)—(C₁-C₆)-alkyl, —C(O)—OH, —C(O)O—(C₁-C₆)-alkyl, —C(O)NR¹⁰R^(10′),—NR¹¹C(O)R¹⁰, —NR¹¹C(O)NR¹⁰R^(10′), —NR¹¹C(O)OR¹⁰, —SO₂(C₁-C₆)-alkyl,—SO₂(C₁-C₆)-haloalkyl, —SO₂-aryl, —SO₂NR¹⁰R^(10′), CN, haloalkyl, andhalogen; R² is hydrogen, (C₁-C₆)-alkyl, or (C₁-C₆)-alkoxy; R³ isunsubstituted (C₁-C₆)-alkyl; R⁴ is hydrogen or (C₁-C₆)-alkyl; R⁵ is—C(O)NR⁶R⁷; R⁶ is hydrogen, (C₁-C₆)-alkyl, aryl, or heterocyclyl, where(C₁-C₆)-alkyl is optionally substituted with one or more substituentsindependently selected from the group consisting of: —OR¹¹, —SR ¹¹, —CN,—F, —Cl, —Br, —I, —NR¹⁰R^(10′), (C₃-C₆)-cycloalkyl, aryl, heterocyclyl,—C(O)—R¹¹, —C(O)—(C₀-C₆)-alkyl-aryl, —C(O)O—R¹¹,—C(O)O—(C₀-C₆)-alkyl-aryl,—C(O)N—R¹⁰R^(10′)—C(O)NR¹¹—(C₀-C₆)-alkyl-aryl, —NR¹¹C(O)—R¹⁰, and—NR¹¹C(O)—(C₀-C₆)-alkyl-aryl; wherein the aryl and heterocyclyl ringsubstituents may be further substituted with one or more groupsindependently selected from the group consisting of (C₁-C₆)-alkyl,halogen, (C₁ ⁻C₆)-haloalkyl, CN, oxo, hydroxy, (C₁-C₆)-alkoxy,—C(O)—(C₁-C₆)-alkyl, and —C(O)—O—(C₁-C₆)-alkyl; and where aryl andheterocyclyl are optionally substituted with (C₁-C₆)-alkyl, halogen,(C₁-C₆)-haloalkyl, CN, oxo, hydroxy, (C₁-C₆)-alkoxy, —C(O)—(C₁-C₆)-alkylor —C(O)—O—(C₁-C₆)-alkyl; R⁷ is hydrogen or (C₁-C₆)-alkyl; or R⁶ and R⁷together with the atom to which they are attached form a saturated orunsaturated 3-8 membered ring, optionally incorporating one, two, orthree additional heteroatoms independently selected from the groupconsisting of N, O, and S atoms, and optionally substituted with oxo,—OH, —SH, —F, —Cl, —Br, —I, —NR¹¹R^(11′), (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,(C₁-C₆)-thioalkyl, (C₁-C₆)-haloalkyl, hydroxy-(C₁-C₆)-alkyl, —C(O )—H,—C(O)—(C₁-C₆)-alkyl, —C(O)OH, or —C(O)O—(C₁-C₆)-alkyl; R¹⁰ and R^(10′)are independently selected from the group consisting of H,(C₁-C₆)-alkyl, (C₁-C₆) -haloalkyl, aryl, -aryl-(C₁-C₆)-alkyl,heteroaryl, heterocyclyl, —C(O)—H, —C(O)—(C₁-C₆)-alkyl, —C(O)-aryl, and—C(O)—(C₁-C₆)-alkyl-aryl; or R¹⁰ and R^(10′) together with the atom towhich they are attached form a saturated or unsaturated 3-8 memberedring, optionally incorporating one, two, or three additional heteroatomsindependently selected from the group consisting of N, 0, and S atoms,and optionally substituted with one or more substituents independentlyselected from the group consisting of oxo, —OH, —F, —Cl, —Br, —I,—NR¹¹R^(11′), (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₁-C₆)-haloalkyl, hydroxy-(C₁-C₆)-alkyl-, —C(O)—H, —C(O)—(C₁-C₆)-alkyl, —C(O)OH, and—C(O)—O—(C₁-C₆)-alkyl; R¹¹ and R^(11′) are independently selected fromthe group consisting of hydrogen and (C₁-C₆)-alkyl; and A is(C₁-C₄)-alkylene, (C₂-C₄)-alkenylene, or (C₂-C₄)-alkynylene; or a salt,a stereoisomer, or a mixture of stereoisomers thereof.
 3. The compoundof claim 2, where R¹, R² and R³ are independently (C₁-C₄)-alkyl; or asalt, a stereoisomer, or a mixture of stereoisomers thereof.
 4. Thecompound of claim 2, where R⁶ is (C₁-C₆)-alkyl optionally substitutedwith one, two or three substituents independently selected from thegroup consisting of —OH, —SH, (C₁-C₄)-alkoxy, (C₁-C₄)-thioalkyl, —CN,—F, —Cl, —Br, —I, —NH₂, —NH(C₁-C₄)-alkyl, and —N((C₁-C₄)-alkyl)₂; or asalt, a stereoisomer, or a mixture of stereoisomers thereof.
 5. Thecompound of claim 2, where R⁶ is (C₁-C₆)-alkyl substituted with aryl,where the aryl is optionally substituted with one, two or threesubstituents independently selected from the group consisting of(C₁-C₆)-alkyl, halogen, (C₁-C₆)-haloalkyl, oxo, hydroxy, (C₁-C₆)-alkoxy,—C(O)—(C₁-C₆)-alkyl, and —C(O)O—(C₁-C₆)-alkyl; or a salt, astereoisomer, or a mixture of stereoisomers thereof.
 6. The compound ofclaim 2, where R⁶ is (C₁-C₆)-alkyl optionally substituted with—NR¹⁰R^(10′), where R¹⁰ and R^(10′) together with the atom to which theyare attached form a saturated or unsaturated 3-8 membered ring,optionally incorporating one, two, or three additional heteroatomsindependently selected from the group consisting of N, O, and S atoms,and optionally substituted with one or more substituents independentlyselected from the group consisting of oxo, —OH, —F, —Cl, —Br, —I,—NR¹¹R^(11′),(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₁-C₆)-haloalkyl,hydroxy-(C₁-C₆)-alkyl-, —C(O)—H, —C(O)—(C₁-C₆)-alkyl, —C(O)OH, and—C(O)—O—(C₁-C₆)-alkyl; or a salt, a stereoisomer, or a mixture ofstereoisomers thereof.
 7. The compound of claim 2, where R⁶ is aryl orheterocyclyl optionally substituted with one, two, or three substituentsindependently selected from the group consisting of (C₁-C₆)-alkyl,halogen, (C₁-C₆)-haloalkyl, CN, oxo, hydroxy, (C₁-C₆)-alkoxy,—C(O)—(C₁-C₆)-alkyl, and —C(O)O—(C₁-C₆)-alkyl; or a salt, astereoisomer, or a mixture of stereoisomers thereof.
 8. The compound ofclaim 2, where R⁴ is hydrogen; or a salt, a stereoisomer, or a mixtureof stereoisomers thereof.
 9. A compound selected from the groupconsisting of:1-ethyl-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;1-(2-hydroxyethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;1-(2-(dimethylamino)ethyl)-3 -(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;3-(2-(dimethylamino)ethyl)-1-methyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;3-ethyl-1-methyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;1-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;1-methyl-1-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;1-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-3-ethylurea;1-(2-morpholinoethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;4-benzyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;1-(pyridin-2-ylmethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;1-(pyridin-4-ylmethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;1-(pyridin-3-ylmethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;4-hydroxy-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;1,1-diethyl-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;1-(4-chlorobenzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;4-methyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;4-acetyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;4-oxo-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;1-(4-fluorobenzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;1-(4-(trifluoromethyl)benzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;1-(4-chlorobenzyl)-1 -methyl-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;3-(4-chlorobenzyl)-1-methyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;4,4-difluoro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;and4-fluoro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;or a salt, a stereoisomer, or a mixture of stereoisomers thereof. 10.The compound of claim 2, additionally comprising a pharmaceuticallyacceptable excipient.
 11. A method of treating or suppressing anoxidative stress disorder comprising administering to a subject atherapeutically effective amount of a compound of claim 1, where theoxidative stress disorder is a mitochondrial disorder selected from thegroup consisting of an inherited mitochondrial disease; MyoclonicEpilepsy with Ragged Red Fibers (MERRF); Mitochondrial Myopathy,Encephalopathy, Lactacidosis, Stroke (MELAS); Maternally InheritedDiabetes and Deafness (MIDD); Leber's Hereditary Optic Neuropathy(LHON); chronic progressive external ophthalmoplegia (CPEO); LeighDisease; Kearns-Sayre Syndrome (KSS); Friedreich's Ataxia (FA);Co-Enzyme Q10 Deficiency; Complex I Deficiency; Complex II Deficiency;Complex III Deficiency; Complex IV Deficiency; Complex V Deficiency;Parkinson's disease; Alzheimer's disease; amyotrophic lateral sclerosis(ALS); muscular dystrophy, and Huntington's Disease.
 12. A method oftreating or suppressing an oxidative stress disorder comprisingadministering to a subject a therapeutically effective amount of acompound of claim 1, where the oxidative stress disorder is an impairedenergy processing disorder, due to deprivation, poisoning or toxicity ofoxygen, or of qualitative or quantitative disruption in the transport ofoxygen.
 13. A method of treating or suppressing a disorder comprisingadministering to a subject a therapeutically effective amount of acompound of claim 1, where the disorder is a hearing or balanceimpairment, or a pervasive development disorder selected from the groupconsisting of Autistic Disorder, Asperger's Disorder, ChildhoodDisintegrative Disorder (CDD), Rett's Disorder, and PDD-Not OtherwiseSpecified (PDD-NOS).
 14. The compound of claim 1, wherein R is

or a salt, a stereoisomer, or a mixture of stereoisomers thereof. 15.The compound of claim 14, wherein R¹, R² and R³ are independently(C₁-C₄)-alkyl; or a salt, a stereoisomer, or a mixture of stereoisomersthereof.
 16. The compound of claim 14, where R⁶ is (C₁-C₆)-alkyloptionally substituted with one, two or three substituents independentlyselected from the group consisting of —OH, —SH, (C₁-C₄)-alkoxy,(C₁-C₄)-thioalkyl, —CN, —F, —Cl, —Br, —I, —NH₂, —NH(C₁-C₄)-alkyl, and—N((C₁-C₄)-alkyl)₂; or a salt, a stereoisomer, or a mixture ofstereoisomers thereof.
 17. The compound of claim 14, where R⁶ is(C₁-C₆)-alkyl substituted with aryl, where the aryl is optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of (C₁-C₆)-alkyl, halogen, (C₁-C₆)-haloalkyl,oxo, hydroxy, (C₁-C₆)-alkoxy, —C(O)—(C₁-C₆)-alkyl, and—C(O)O—(C₁-C₆)-alkyl; or a salt, a stereoisomer, or a mixture ofstereoisomers thereof.
 18. The compound of claim 14, where R⁶ is(C₁-C₆)-alkyl optionally substituted with —NR¹⁰R^(10′) where R¹⁰ andR^(10′) together with the atom to which they are attached form asaturated or unsaturated 3-8 membered ring, optionally incorporatingone, two, or three additional heteroatoms independently selected fromthe group consisting of N, O, and S atoms, and optionally substitutedwith one or more substituents independently selected from the groupconsisting of oxo, —OH, —F, —Cl, —Br, —I, —NR¹¹R^(11′), (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy, (C₁-C₆)-haloalkyl, hydroxy-(C₁-C₆)-alkyl-, —C(O)—H,—C(O)—(C₁-C₆)-alkyl, —C(O)OH, and —C(O)—O—(C₁-C₆)-alkyl; or a salt, astereoisomer, or a mixture of stereoisomers thereof.
 19. The compound ofclaim 14, where R⁶ is aryl or heterocyclyl optionally substituted withone, two, or three substituents independently selected from the groupconsisting of (C₁-C₆)-alkyl, halogen, (C₁-C₆)-haloalkyl, CN, oxo,hydroxy, (C₁-C₆) -alkoxy, —C(O)—(C₁-C₆)-alkyl, and —C(O)O—(C₁-C₆)-alkyl;or a salt, a stereoisomer, or a mixture of stereoisomers thereof. 20.The compound of claim 14, where R⁴ is hydrogen; or a salt, astereoisomer, or a mixture of stereoisomers thereof.
 21. The compound ofclaim 2, where R⁶ and R⁷ together with the atom to which they areattached form a saturated or unsaturated 3-8 membered ring, optionallyincorporating one, two, or three additional heteroatoms independentlyselected from the group consisting of N, O, and S atoms, and optionallysubstituted with oxo, —OH, —SH, —F, —Cl, —Br, —I, —NR¹¹R^(11′), (C_(i)C₆)-alkyl, (C₁-C₆)-alkoxy, (C₁-C₆)-thioalkyl, (C₁-C₆)-haloalkyl,hydroxy-(C₁-C₆)-alkyl, —C(O)—H, —C(O)—(C₁-C₆)-alkyl, —C(O)OH, or—C(O)O—(C₁-C₆)-alkyl; or a salt, a stereoisomer, or a mixture ofstereoisomers thereof.
 22. The compound of claim 14, where R⁶ and R⁷together with the atom to which they are attached form a saturated orunsaturated 3-8 membered ring, optionally incorporating one, two, orthree additional heteroatoms independently selected from the groupconsisting of N, O, and S atoms, and optionally substituted with oxo,—OH, —SH, —F, —Cl, —Br, —I, —NR¹¹R^(11′), (C₁ C₆) alkyl, (C₁-C₆)-alkoxy,(C₁-C₆)-thioalkyl, (C₁-C₆)-haloalkyl, hydroxy-(C₁-C₆)-alkyl, —C(O)—H,—C(O)—(C₁-C₆)-alkyl, —C(O)OH, or —C(O)O—(C₁-C₆)-alkyl; or a salt, astereoisomer, or a mixture of stereoisomers thereof.